Abstract
Patients with advanced-stage or treatment-resistant colorectal cancer (CRC) face limited therapeutic options with conventional therapies, necessitating novel treatment strategies. CRC cells exhibit "lysosomal addiction" through enhanced autophagy-lysosomal flux and upregulated lysosome-associated genes including lysosomal-associated membrane protein 1/2 and cathepsin B/D, creating therapeutic windows for selective targeting. Lysosome-dependent cell death represents a distinct mode of regulated cell death characterized by lysosomal membrane permeabilization and cathepsin-mediated cytotoxic cascades, offering advantages over apoptosis-dependent mechanisms. Recent investigations have identified multiple druggable targets within lysosomal pathways, including autophagy modulators, cathepsin inhibitors, and innovative drug delivery systems. Lysosomes also play bidirectional roles in tumor immune microenvironment regulation, with implications for combination immunotherapy strategies. However, challenges remain in clinical translation, including autophagy's dual functionality and the need for reliable biomarkers. Targeting lysosomal dysfunction represents a promising therapeutic approach for CRC, particularly for overcoming resistance to traditional therapies. The unique metabolic dependency of cancer cells on lysosomal function provides exploitable therapeutic windows for precision medicine approaches.
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Introduction
Colorectal cancer (CRC) represents one of the most formidable challenges in modern oncology, ranking as the third most common malignancy worldwide with 1.93 million new cases and 935,000 deaths annually according to GLOBOCAN 2022 data [1, 2]. Despite decades of therapeutic advances encompassing surgical resection, chemotherapy, targeted therapy, and immunotherapy, treatment resistance remains the predominant factor determining disease outcome [3]. The sobering reality is that metastatic CRC maintains a 5-year survival rate below 15%, with most patients eventually developing resistance to conventional therapies [4]. This therapeutic resistance is particularly pronounced in microsatellite-stable CRC, where single-agent immunotherapy demonstrates limited efficacy with response rates of merely 5–10% [5]. The persistent challenge of treatment resistance underscores an urgent need for novel therapeutic strategies that can overcome the adaptive mechanisms employed by cancer cells to evade cytotoxic interventions.
Cancer cells exhibit remarkable adaptability in developing resistance mechanisms that span genetic, epigenetic, proteomic, and microenvironmental dimensions. Similar to how metastatic cancer cells must overcome multiple obstacles during dissemination, including detachment-induced cell death, immune surveillance, and microenvironmental stress, resistant cancer cells develop sophisticated survival strategies that enable them to withstand therapeutic pressure [6]. Among these survival mechanisms, the dysregulation of lysosomal function has emerged as a critical yet underexplored vulnerability. Lysosomes, traditionally viewed as cellular “waste disposal units,” have been reconceptualized as dynamic regulators of cellular homeostasis and key players in cancer pathogenesis. Cancer cells frequently exhibit what can be termed “lysosomal addiction”—a metabolic dependency characterized by enhanced autophagy-lysosomal flux and significant upregulation of lysosome-associated genes including lysosomal-associated membrane protein 1/2 and cathepsin B/D. Genomic analyses reveal that over 60% of primary CRC tumors demonstrate this lysosomal gene upregulation pattern, creating a distinctive molecular signature that distinguishes malignant from normal tissue [7].
This lysosomal dependency creates an exploitable therapeutic window through multiple convergent mechanisms. Unlike normal cells, which maintain lysosomal homeostasis within narrow parameters, cancer cells push lysosomal systems to their functional limits to support aberrant metabolic demands, enhanced protein turnover, and resistance to cell death signals [8]. This heightened dependency renders cancer cells vulnerable to lysosomal targeting strategies that would be tolerated by normal tissues. Emerging evidence demonstrates that compounds such as dimeric quinacrine 661 can induce tumor-specific cytotoxicity through lysosomal biogenesis overload, exploiting this unique vulnerability [9]. Furthermore, lysosomal targeting offers advantages over conventional approaches by simultaneously addressing both cancer cell-intrinsic resistance mechanisms and tumor microenvironment-mediated protection.
The convergence of lysosomal dysfunction with CRC pathogenesis marks a paradigm shift in our understanding of tumor vulnerabilities. Cancer cells systematically hijack lysosomal mechanisms to meet their elevated metabolic demands while utilizing these pathways to evade conventional apoptotic cell death. This dual exploitation creates multiple therapeutic opportunities: disrupting cancer cell metabolism, inducing alternative cell death pathways, and modulating the immune microenvironment. This review consolidates current understanding of lysosomal biology in CRC, systematically evaluates preclinical evidence for therapeutic strategies targeting lysosomal dysfunction, and explores the translational potential of lysosome-targeting drugs in conquering this malignant disease.
Literature search strategy
Our study strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for literature search, screening, and reporting [10]. This approach ensured process transparency and reproducibility, thereby strengthening the credibility of our conclusions [11].
We conducted a comprehensive literature search through Medline, Web of Science, and Embase databases, covering the period from database inception to May 2025. The aim was to identify studies related to lysosomal biology and CRC treatment. Our search strategy combined Medical Subject Headings terms and free-text keywords using Boolean operators: (“Lysosomes” OR “Autophagy” OR “Lysosome-Associated Membrane”) AND (“Colorectal Neoplasms” OR “Colonic Neoplasms” OR “Rectal Neoplasms”) AND (“Tumor Microenvironment” OR “Molecular Targeted Therapy” OR “Targeted Therapy” OR “Immunotherapy”).
The inclusion criteria encompassed original research articles, reviews, and clinical studies published in peer-reviewed English journals. Specifically, we included studies involving lysosomal biology in cancer, lysosome-dependent cell death (LDCD) mechanisms and autophagy regulation, clinical trials or basic research on lysosome-targeting drugs for CRC treatment, and the role of lysosomes in the tumor immune microenvironment. We excluded conference abstracts, case reports, and editorial comments lacking substantial data. We also excluded studies focusing solely on lysosomal storage diseases unrelated to cancer, articles with insufficient methodological details or unclear results, and duplicate publications with overlapping data. The screening process involved an initial review of titles and abstracts. This was followed by full-text evaluation of potentially relevant articles. We ultimately determined study inclusion based on relevance to lysosomal mechanisms in CRC pathogenesis, therapeutic targeting strategies, and clinical significance.
Lysosomal structure and function
Basic structure of lysosomes
Lysosomes are dynamic, acidic organelles (pH 4.5–5.0) enclosed by a specialized single-membrane bilayer (7–10 nm thick) that serves as both a protective barrier and a regulatory interface [12, 13]. The lysosomal membrane maintains the organelle’s acidic environment through the vacuolar H⁺-ATPase (v-ATPase), a multi-subunit complex that actively transports protons into the lumen using adenosine triphosphate hydrolysis [14]. A protective glycocalyx layer, approximately 8 nm thick [15], is formed through extensive glycosylation of lysosome-associated membrane proteins [16], preventing auto-digestion by the organelle’s more than 60 acid hydrolases, including cathepsins, sphingomyelinases, and α-glucosidases [17]. The targeting and delivery of lysosomal enzymes follows a highly regulated pathway. Hydrolases are initially synthesized on ribosomes of the rough endoplasmic reticulum (ER), then transported to the cis-Golgi apparatus where they undergo N-linked glycosylation and mannose phosphorylation to acquire mannose-6-phosphate (M6P) recognition signals [18]. M6P receptors in the trans-Golgi network specifically recognize these modified enzymes and package them into clathrin-coated vesicles [19]. Under the regulation of ras-related in brain GTPases and effector proteins, these vesicles undergo microtubule-dependent transport and fusion with early endosomes or lysosomes, ensuring precise enzyme delivery [20, 21]. Membrane permeability is tightly controlled by specialized regulatory proteins, notably transient receptor potential mucolipin 1(TRPML1), which functions as a Ca2⁺ release channel [22]. TRPML1 responds to changes in lysosomal pH and second messengers such as phosphatidylinositol 3,5-bisphosphate, mediating membrane fusion and content recycling processes [23].
Lysosomes exhibit remarkable morphological plasticity, dynamically transitioning between spherical, tubular, and network-like structures [24, 25]. This structural flexibility is directly controlled by membrane lipid composition, which regulates membrane fluidity and mechanical stability by modulating lipid bilayer microviscosity [26]. The threshold for lysosomal membrane permeabilization (LMP) is determined by protein-lipid cooperative interactions with significant pathological implications. Lysosome-associated membrane protein 1 (LAMP1) anchors to the cytoskeleton through its cytoplasmic tail domain, and its deficiency increases membrane sensitivity to cathepsin B leakage by 3–fivefold [27, 28]. Similarly, the depletion of cholesterol in the membrane lipid raft leads to the collapse of the H⁺ gradient and the acceleration of LMP progression [29, 30].
These structural alterations have direct clinical relevance in cancer progression. In CRC, aberrant glycosylation of key proteins disrupts normal cellular functions through multiple validated mechanisms. For example, altered N-glycosylation of tissue inhibitor of metalloproteinase-1 affects its binding properties with matrix metalloproteinases, increasing cancer cell invasiveness [31]. Similarly, changes in glycosylation patterns can modify protein–protein interactions and cellular adhesion properties, contributing to enhanced metastatic potential [32]. While lysosomal membrane proteins like lysosome-associated membrane protein 2 undergo significant glycosylation changes in cancer, their specific contributions to tumor progression mechanisms warrant further investigation [16]. These findings underscore how lysosomal membrane integrity critically influences both normal cellular homeostasis and disease pathogenesis.
Lysosomal functions
Metabolic regulation and cellular homeostasis
Lysosomes operate as highly dynamic degradation and recycling centers through sophisticated molecular networks that maintain cellular homeostasis [33]. The organelle quality control system relies on selective autophagy pathways that ensure efficient clearance of damaged cellular components. Autophagy-mediated clearance occurs through two principal mechanisms. Macroautophagy involves UNC-51-like kinase 1 (ULK1) kinase complex activation, leading to autophagosome formation that engulfs damaged mitochondria and ER fragments through light chain 3 (LC3) lipidation-marked membrane structures [34, 35]. These autophagosomes undergo ras-related protein Rab-7 (Rab7)-regulated docking with lysosomes [36], followed by soluble NSF attachment protein receptor (SNARE) protein-mediated membrane fusion and content release into the lysosomal lumen [37]. Simultaneously, chaperone-mediated autophagy (CMA) provides substrate-specific degradation of aberrant proteins. This process relies on heat shock cognate 70 (HSC70) and co-chaperone proteins that specifically recognize KFERQ motif-containing proteins [38]. These targeted proteins are then translocated across lysosomal membranes through lysosome-associated membrane protein 2A (LAMP2A) multimeric channels, with assistance from heat shock protein 90 (HSP90) [39], as shown in Fig. 1. Metabolic substrate processing involves precise enzymatic degradation of toxic substances, including lipofuscin and advanced glycation end products (AGEs) [40]. Glucosylceramidase beta 1, assisted by saposin C, catalyzes glycosphingolipid metabolism, while cathepsin K specifically cleaves AGE cross-linked structures [41]. The sequestosome-1 (SQSTM1/p62)-mediated ubiquitin-autophagy system clears protein aggregates, with degradation products recycled via transporters such as ATPase phospholipid transporting 8B1 to generate amino acids and fatty acids for biosynthetic pathways [42]. This dynamic equilibrium is regulated by the mechanistic target of rapamycin complex 1 (mTORC1)-transcription factor EB (TFEB) signaling axis. This regulatory pathway senses lysosomal amino acid levels and coordinates the expression of over 130 genes. As a result, it synchronously upregulates both autophagy and lysosomal biogenesis [43, 44]. The Rab7-TRPML1-Ca2⁺ signaling network controls bidirectional lysosomal transport along microtubule networks, while TRPML1-mediated Ca2⁺ release triggers lysosome-endosome fusion and promotes autophagosome maturation [33, 45, 46], as shown in Fig. 2.
Lysosomal nutrient sensing and degradation pathways
Lysosomal degradation pathways and cellular homeostasis maintenance
Cellular energy sensing
Lysosomes function as central energy-sensing hubs that integrate lipid signaling, phosphorylation modifications, and inter-organellar communication to dynamically regulate metabolic and stress responses. The lysosomal surface forms a dynamic sensing network through v-ATPase, mTORC1, and AMP-activated protein kinase (AMPK) signaling complexes [47].
During nutrient abundance, mTORC1 responds to phosphatidylinositol-3-phosphate (PI(3)P) lipid signals and drives anabolic metabolism. In contrast, under energy stress conditions, a different pathway is activated. Phosphatidylinositol-4-phosphate (PI(4)P) mediates the inhibition of v-ATPase activity, which subsequently activates AMPK and triggers catabolic adaptation [48], as shown in Fig. 1. The lysosomal cholesterol signaling protein couples lysosomal cholesterol levels with cellular growth signals by binding cholesterol and regulating mTORC1 complex activity [49].
Clinical implications of lysosomal energy sensing are particularly evident in cancer metabolism. This signaling axis drives tumor metabolic reprogramming by sensing amino acids and cholesterol to promote protein and lipid synthesis supporting cancer cell proliferation [50]. Conversely, lysosome-dependent AMPK pathways represent important tumor suppressor nodes that can be therapeutically exploited. Metformin, a widely used antidiabetic drug with established anti-cancer properties, exemplifies this therapeutic potential by activating AMPK through multiple coordinated mechanisms: it directly targets presenilin enhancer 2, leading to downstream mTORC1 inhibition and restoration of cellular energy homeostasis. Similarly, lithocholic acid mimics caloric restriction effects through v-ATPase subunit V1E1 deacetylation, and together these compounds synergistically suppress tumor growth by redirecting cellular metabolism from anabolic to catabolic pathways [51, 52]. Notably, v-ATPase-mediated tumor microenvironment acidification not only enhances extracellular matrix degradation to promote metastasis but also regulates immune escape and distant colonization through autophagy-dependent extracellular vesicle release mechanisms [53, 54].
Immune defense functions
Lysosomal immune defense functions encompass innate immunity, adaptive immunity, and immune homeostasis maintenance [55, 56]. In adaptive immune responses, lysosomes achieve antigen presentation precision through spatiotemporal dynamic regulation [57].
Antigen presentation pathways demonstrate sophisticated lysosomal control mechanisms. Dendritic cells utilize lysosomal proteases to degrade exogenous antigens into peptides that bind major histocompatibility complex (MHC) class II molecules for CD4-positive T cell activation [58]. Cross-presentation optimizes MHC class I antigen presentation through two distinct mechanisms. First, NADPH oxidase 2 induces phagosome alkalization. This alkaline environment inhibits cysteine protease activity, thereby preventing excessive antigen degradation [59]. Second, Toll-like receptor signaling activates a spatial reorganization pathway. This involves Rab34-mediated lysosomal rearrangement, which delays phagosome fusion and reduces lysosomal protease expression driven by TFEB activity [60]. Immune effector mechanisms balance cytotoxicity with self-protection. CD8-positive T cells release lysosome-derived granules that induce target cell apoptosis. To prevent self-damage, serpin family B member 9 inhibits granzyme B activity within the T cell itself. This creates a "dual-lock mechanism" that ensures immune attack specificity [61, 62]. Additionally, lysosomes regulate dendritic cell maturation through the TRPML1-Ca2⁺-TFEB axis, with Ca2⁺ release promoting MHC molecule expression and activating migration-related genes [63], as shown in Fig. 3. These integrated lysosomal functions underscore their central role in cellular homeostasis and highlight their potential as therapeutic targets in metabolic disorders, cancer, and immune-related diseases.
Lysosomal immune defense mechanisms
Lysosomal programmed cell death mechanisms
Molecular basis of LDCD
LDCD represents a distinct mode of cellular demise characterized by LMP leading to the cytosolic release of lysosomal contents and subsequent activation of cell death signaling cascades [64]. The fundamental mechanism underlying this process involves the ectopic activation of lysosomal hydrolases, particularly the cathepsin family of proteases, which subsequently trigger cell death through multiple signaling pathways [65]. Lysosomal membrane stability is precisely regulated by diverse endogenous and exogenous factors. Under physiological conditions, B-cell lymphoma 2 (Bcl-2) family proteins maintain membrane integrity through their interaction with lysosomal membranes [66], whilst heat shock protein 70 protects membrane structures from stress-induced damage through its molecular chaperone function [67]. However, when cells are exposed to oxidative stress, ionizing radiation, chemotherapeutic agents, or inflammatory mediators, the accumulation of lipid messenger molecules such as ceramide within the membrane disrupts the integrity of the bilayer, leading to LMP [68,69,70]. Upon LMP, lysosomal cathepsin B, D, L, and other cysteine and aspartate proteases are released into the cytosol [71]. Despite the suboptimal neutral pH environment of the cytoplasm, these enzymes retain sufficient proteolytic activity to trigger programmed cell death [72]. This process is mediated through two principal molecular pathways. The first pathway involves cathepsin-mediated cleavage of the BH3-interacting domain death agonist (Bid), generating its truncated form truncated Bid (tBid) [73]. tBid then translocates to the mitochondrial outer membrane and induces mitochondrial outer membrane permeabilization. This leads to cytochrome c release and activation of the apoptosome complex, ultimately initiating caspase-9-dependent apoptotic execution [74]. The second pathway allows proteases to directly manipulate apoptotic regulators. These enzymes can degrade anti-apoptotic proteins such as Bcl-2 and X-linked inhibitor of apoptosis protein. They can also activate pro-apoptotic factors like Bcl-2-associated X protein or even bypass apoptosome activation through direct cleavage of procaspase-3 [73]. Beyond proteolytic enzyme release, LDCD involves the aberrant release of lysosomal ions and small molecule metabolites. Under pathological conditions, lysosomal membrane damage leads to massive zinc efflux through upregulated TRPML1 channels, which can directly activate necrotic cell death pathways, playing a crucial role in certain malignancies such as metastatic melanoma [75, 76]. Simultaneously, abnormal release from the lysosomal iron pool triggers a cascade of damaging reactions. The released iron catalyzes lipid peroxidation through the Fenton reaction, significantly increasing intracellular reactive oxygen species (ROS) levels. This elevated ROS not only exacerbates oxidative damage but can also trigger ferroptosis, a recently discovered form of cell death [77, 78].
Furthermore, disruption of lysosomal pH homeostasis constitutes another important dimension of LDCD. In certain metabolic diseases, alkaline metabolic products such as ammonia accumulate abnormally within lysosomes, neutralizing their acidic environment and elevating pH [79]. This pH alteration not only causes the inactivation of pH-sensitive enzymes such as cathepsins but also leads to the accumulation of undegraded substrates, including misfolded proteins and lipids, within lysosomes [80]. These unprocessed substrates subsequently trigger mitochondrial dysfunction through incompletely understood mechanisms and amplify cell death signal transmission [81]. The molecular mechanisms of LDCD demonstrate remarkable evolutionary conservation. In Caenorhabditis elegans, individuals lacking the cysteine protease inhibitor srp-6 undergo widespread cell death due to uncontrolled LMP and leakage of cathepsins CPP-1/3 [82], indicating that lysosomal homeostasis is a highly conserved feature critical for cell survival across multicellular organisms.
In summary, LDCD represents a critical node in the cellular death regulatory network, integrating multiple lethal signals including proteolysis, ionic imbalance, oxidative stress, and metabolic disruption through the loss of lysosomal membrane integrity. A comprehensive understanding of this complex signaling network not only contributes to elucidating fundamental mechanisms of cell death but also provides novel therapeutic targets for related diseases (Table 1).
Autophagy-dependent cell death
Autophagy-dependent cell death (ADCD) represents a distinct mode of cellular demise characterized by aberrant activation and dysregulation of the autophagic process culminating in ultimate cell death [83]. Unlike classical apoptosis and necrosis, the fundamental mechanism of ADCD involves the transition of autophagy from a cytoprotective response to a lethal process, a conversion that requires precise regulation and intricate interplay of multiple molecular events.
The pathological process of ADCD originates from abnormal activation of autophagic signaling pathways. Several conditions can trigger this process, including nutrient deprivation, oxidative stress, or specific pharmacological interventions such as rapamycin treatment. Under these conditions, the mammalian target of rapamycin (mTOR) signaling pathway becomes inhibited. This inhibition subsequently activates the unc-51 like autophagy activating kinase 1 (ULK1) complex [84]. This initial event triggers the Beclin-1/VPS34 complex-mediated autophagosome nucleation process and lipidation modification of microtubule-associated protein 1 LC3, ultimately promoting autophagosome membrane formation and maturation [85]. In physiological autophagy, this process is subject to stringent spatiotemporal regulation to maintain cellular homeostasis. However, in ADCD, sustained and excessive autophagy activation leads to overconsumption of cellular resources, including massive depletion of ATP and abnormal degradation of essential cellular components such as proteins and organelles [86]. More critically, the generation of abundant autophagosomes significantly increases their fusion frequency with lysosomes, resulting in excessive burden and ultimate depletion of the lysosomal enzyme system whilst compromising lysosomal membrane structural integrity [87]. Lysosomal dysfunction triggered by excessive autophagy activation constitutes a critical pathological component of ADCD. LMP plays a central role in this process. It occurs through coordinated regulation by multiple factors. These factors include accumulation of ROS, abnormal generation of sphingolipid metabolites, and proteolytic cleavage of BH3 interacting-domain death agonist protein [88]. LMP leads to cytosolic release of lysosomal contents, particularly hydrolytic enzymes such as cathepsins. Although these enzymes show reduced activity in the cytoplasmic environment, they remain capable of promoting abnormal autophagy activation. This creates a pathological positive feedback loop that perpetuates the destructive process [89].
The mTOR/AMPK energy-sensing axis serves as the primary regulatory checkpoint in cellular energy homeostasis. When this axis becomes dysregulated, it directly influences both autophagy initiation and maintenance processes [90]. When mTOR activity is inhibited or AMPK is abnormally activated, the phosphorylation-mediated inhibition of the ULK1 complex is released. This leads to aberrant massive autophagosome generation. The excessive autophagosome formation subsequently causes energy depletion in the cell [91]. Under mTOR inhibition conditions, TFEB is activated and promotes transcription of lysosomal biogenesis-related genes, theoretically enhancing cellular degradative capacity [92]. However, in ADCD, this compensatory response is often insufficient to meet the demands of excessive autophagy. Instead, it leads to lysosomal system overload. This overload increases LMP risk and further compromises lysosomal stability.
The distinctive feature of ADCD lies in its complex cross-talk with other forms of cell death. During autophagy, the anti-apoptotic protein Bcl-2 undergoes selective degradation. This relieves the inhibition of pro-apoptotic proteins, including Bcl-2-associated X protein and Bcl-2-associated K protein. The activation of these pro-apoptotic proteins increases mitochondrial outer membrane permeability. This leads to cytochrome c release and subsequent caspase cascade activation [93]. This mechanism closely links autophagic cell death with the classical mitochondrial apoptotic pathway. Furthermore, cathepsins B and D leaked from lysosomes can cleave Bid protein to generate its truncated active form tBid, further amplifying mitochondrial apoptotic signals [72]. Simultaneously, two parallel processes occur: ROS accumulation and disruption of intracellular calcium homeostasis. These processes activate calpain and receptor-interacting protein kinase 1/3 (RIPK1/3)-mediated necroptotic pathways. The activation of these pathways forms multiple positive feedback loops. These loops work synergistically to promote cell death [94].
In summary, ADCD represents a complex pathological mechanism involving the transition of cellular autophagy from an adaptive response to a lethal process. The multi-level regulatory networks involved in ADCD and their cross-talk with other forms of cell death have important implications. These complex interactions enrich our understanding of cell death regulatory mechanisms. Additionally, they provide novel theoretical foundations for developing therapeutic strategies for related diseases (Table 2).
Lysosomal and CRC
Lysosomal dysfunction and tumorigenesis
Lysosomal dysfunction drives tumor metabolism and proliferation
Lysosomes serve as central hubs for tumor cell metabolic reprogramming through their regulation of catabolic processes and nutrient recycling [95]. Within the nutrient-depleted tumor microenvironment, the autophagy-lysosomal system sustains rapid tumor cell proliferation by degrading macromolecules including proteins and lipids to release metabolic precursors such as amino acids and fatty acids [96]. This metabolic adaptation is exemplified in pancreatic ductal adenocarcinoma (PDAC). In PDAC, mTORC1 becomes inactivated. This inactivation promotes nuclear translocation of microphthalmia/transcription factor E family transcription factors. The nuclear translocation activates autophagy and lysosomal catabolism. It also enhances lysosomal biogenesis. These processes work together to restore amino acid homeostasis and support continued tumor growth [97, 98].
Lysosomal dysfunction further contributes to tumorigenesis through its impact on cell cycle regulatory protein degradation and recycling. In hepatocellular carcinoma (HCC), elevated ADP-ribosylation factor-like 8B (ARL8B) expression maintains lysosomal acidification function whilst inhibiting degradation of key cyclin proteins. Genetic silencing of ARL8B induces G0/G1 phase arrest and significantly reduces tumor burden, highlighting the pivotal role of the lysosomal–cell cycle axis in tumor progression [98, 99]. These findings underscore the fundamental importance of lysosomal homeostasis in controlling both metabolic flux and cell cycle progression in malignant transformation.
Lysosomal-mediated tumor microenvironment remodeling and immune evasion
Lysosomal dysfunction drives tumor invasion and the formation of immunosuppressive microenvironments through secretion of enzymatic factors and modulation of immune cell infiltration [56, 100]. Tumor cells utilize ras-related protein Rab-27A-dependent mechanisms to secrete lysosomal proteases, including cathepsins and matrix metalloproteinases, into the extracellular matrix, promoting collagen degradation and activating invasive signaling pathways [101]. This process is particularly pronounced at the invasive front of pancreatic cancer and melanoma [102, 103]. Concurrently, lysosomal abnormalities reshape the immune landscape through complex mechanisms. HCC cases with elevated ARL8B expression exhibit characteristic lysosomal dysfunction. This dysfunction triggers the infiltration of tumor-associated neutrophils into the tumor microenvironment. Once recruited, these neutrophils become key players in immune suppression. They suppress CD8-positive T cell function through two distinct mechanisms. The first mechanism involves causing ROS-mediated genomic damage to T cells. The second mechanism involves the active secretion of immunosuppressive cytokines, specifically interleukin-10 and transforming growth factor-beta. The combination of direct cellular damage and cytokine-mediated suppression creates a powerful dual pro-tumorigenic mechanism. This mechanism effectively shields the tumor from immune surveillance and promotes continued tumor progression [99, 104]. This lysosomal-driven microenvironmental remodeling provides a critical pathological foundation for tumor metastasis and resistance to immunotherapy.
Lysosomal dysfunction and tumor drug resistance
Lysosomes have emerged as critical orchestrators of chemotherapeutic resistance, operating through multiple interconnected mechanisms that extend far beyond their traditional role in cellular waste disposal. These organelles function as important mediators of chemotherapeutic resistance through sophisticated drug efflux mechanisms, activation of non-apoptotic death pathways, and complex alterations in cellular stress responses that collectively compromise therapeutic efficacy [105].
At the forefront of these resistance mechanisms is the phenomenon of lysosomal drug sequestration, which represents a fundamental obstacle to effective chemotherapy across diverse cancer types. Weakly basic chemotherapeutic agents, including anthracyclines, tyrosine kinase inhibitors, and various targeted therapies, become protonated and trapped within the acidic lysosomal lumen through a process termed lysosomal drug accumulation [106]. This sequestration effectively reduces cytoplasmic and nuclear drug concentrations, shielding critical therapeutic targets from drug action. Building upon this basic sequestration mechanism, cancer cells have evolved sophisticated efflux systems to actively eliminate trapped drugs. In rhabdomyosarcoma, for instance, reduced neuraminidase 1 expression leads to LMP and migration toward the cell membrane, facilitating SNARE protein-dependent exocytosis of anthracycline drugs and consequently reducing intracellular drug concentrations [107]. This exocytic mechanism is further amplified by increased lysosomal biogenesis mediated by TFEB activation, which expands the cellular capacity for drug sequestration and subsequent efflux.
Complementing these sequestration and efflux mechanisms, the ATP-binding cassette transporter family provides an additional layer of drug resistance at the lysosomal level. P-glycoprotein localizes to lysosomal membranes in resistant cancer cells, actively pumping drugs into lysosomes where they become trapped and eventually expelled through exocytosis. This lysosomal P-glycoprotein expression correlates strongly with multidrug resistance phenotypes and poor clinical outcomes [108]. Additionally, the lysosomal calcium channel TRPML1 regulates lysosomal exocytosis and has been implicated in facilitating drug efflux, suggesting that calcium signaling pathways represent potential therapeutic targets for overcoming lysosomal-mediated resistance [109]. These transport mechanisms work in concert with the acidic lysosomal environment to create a formidable barrier to drug efficacy.
Beyond their role in drug sequestration and efflux, lysosomes contribute to resistance by modulating cell death pathways. When conventional apoptotic pathways are compromised, as frequently occurs in resistant tumors, lysosomal membrane permeabilization triggers alternative death mechanisms. Photosensitizers disrupt mitochondrial-lysosomal interactions, inducing increased LMP whilst activating ferroptosis through acyl-CoA synthetase long-chain family member 4-dependent lipid peroxidation and pyroptosis via gasdermin D cleavage pathways [110]. This plasticity in cell death mechanisms suggests that targeting lysosomes could overcome apoptosis resistance by engaging alternative death pathways [111]. The ability of cancer cells to switch between different death modalities based on lysosomal status represents a sophisticated survival strategy that must be considered in therapeutic design.
Central to both drug resistance and cell death regulation is the cathepsin family of lysosomal proteases, which contributes to resistance through both degradative and signaling functions [80]. Cathepsins B, L, and D, when released into the cytoplasm following LMP, can cleave and inactivate pro-apoptotic proteins while simultaneously activating survival signaling cascades including nuclear factor-κB and mitogen-activated protein kinase pathways [112]. Moreover, cathepsin-mediated degradation of chemotherapeutic agents themselves has been documented, directly reducing drug bioavailability [113]. The extracellular release of cathepsins further promotes an invasive, therapy-resistant phenotype through extracellular matrix remodeling and activation of protease-activated receptors [114].
Underlying all these resistance mechanisms is the maintenance of lysosomal acidic pH by the v-ATPase, which is essential for drug sequestration and resistance. Inhibition of v-ATPase alkalinizes lysosomes, releasing trapped drugs and restoring therapeutic sensitivity [115]. However, cancer cells often exhibit compensatory mechanisms, including increased expression of v-ATPase subunits and enhanced buffering capacity, maintaining lysosomal acidification despite therapeutic intervention [116]. This pH regulation extends beyond drug sequestration, influencing autophagy, mTOR signaling, and metabolic adaptation, which are all critical determinants of therapeutic response.
Collectively, these discoveries reveal the translational potential of targeting lysosomal membrane stability or exocytic pathways in overcoming drug resistance. Combination strategies incorporating lysosomal disrupting agents with conventional chemotherapy show promise in preclinical models. Meanwhile, novel approaches are emerging that target specific lysosomal components. These approaches focus on lysosomal calcium channels, sphingolipid metabolism, and membrane dynamics. Both conventional combinations and novel targeted approaches offer significant additional therapeutic opportunities for improving cancer treatment outcomes.
Lysosomal in CRC research
The role of lysosome-regulated autophagy in CRC development and progression
As the central organelle of the cellular degradation system, lysosomes maintain colorectal epithelial cell homeostasis through precise regulation of autophagy processes. Dysfunction of this system represents a crucial driver of tumorigenesis. Within the macroautophagy pathway, lysosomes play a central role in processing autophagosomal contents. They mediate the uptake of these contents through specific membrane fusion proteins, including syntaxin-17 and synaptosomal-associated protein 29. Following successful uptake, lysosomes complete substrate degradation using acidic hydrolases such as cathepsin B and cathepsin D [117]. CRC cells frequently exhibit aberrant macroautophagy activation accompanied by enhanced lysosomal biogenesis, characterized by upregulation of LAMP1 expression and increased lysosomal acid phosphatase activity [118].
Recent investigations have demonstrated that tea polysaccharides induce autophagic cell death in human colon tumor cell line 116 (HCT116) cells. The process begins with mTOR kinase inhibition. This inhibition promotes nuclear translocation of TFEB. Once in the nucleus, TFEB induces transcription of key lysosomal genes, including LAMP1 and cathepsin B. This process enhances autophagolysosomal flux, ultimately leading to degradation of oncogenic proteins [119]. Beyond macroautophagy, CMA plays a pivotal role in tumor immune evasion. The core effector molecule LAMP2A recognizes substrate proteins bound by HSC70, including immune checkpoint molecules, and mediates their lysosomal degradation. Emerging evidence indicates that inhibition of fucosyltransferase 8 (FUT8) triggers a cascade of molecular events. FUT8 inhibition causes deglycosylation modifications of B7 homolog 3 (B7-H3). These modifications expose the 106–110 SLRLQ motif within B7-H3. The exposed motif enhances HSC70 recognition efficiency. This improved recognition promotes B7-H3 degradation via the CMA pathway. Ultimately, B7-H3 degradation suppresses tumor immune evasion and metastasis. Clinical data analysis further reveals that patients with high FUT8 expression demonstrate significantly higher B7-H3 positivity rates in tumor tissues compared to those with low FUT8 expression, correlating with poor prognosis [120].
Mechanisms of LMP in CRC cell death
LMP resulting from compromised lysosomal membrane integrity represents a critical executioner mechanism in CRC cell death. This process is primarily triggered through two distinct mechanisms: oxidative stress characterized by ROS accumulation, and drug-induced lysosomal damage [121, 122]. When lysosomal membrane bilayer stability is compromised, cathepsins including cathepsin B and cathepsin D are released into the cytoplasm, subsequently activating downstream apoptotic signaling pathways. At the molecular level, cathepsin B specifically cleaves Bid protein to generate truncated tBid, which induces mitochondrial permeability transition pore opening. This process promotes cytochrome c release and caspase-9/-3 cascade activation, forming a distinctive “lysosome-mitochondria apoptotic axis” [123, 124]. The mechanism of action of periplocin provides a paradigmatic example of this therapeutic approach. Periplocin is an active component derived from traditional Chinese medicine. It exerts its effects by binding to the Galectin-3 protein. This binding inhibits ubiquitination-mediated degradation specifically at the K210 site. The inhibition of degradation induces excessive lysosomal autophagy. This excessive autophagy ultimately leads to lysosomal membrane phospholipid peroxidation. The peroxidation then triggers LMP occurrence, completing the cytotoxic cascade [125].
Beyond apoptotic pathways, lysosomal iron homeostasis imbalance plays a crucial role in ferroptosis regulation. Studies demonstrate that dichloroacetic acid chelates Fe2⁺ within lysosomes, inducing accumulation of lipid peroxidation product 4-hydroxynonenal, thereby specifically targeting CRC stem cells. This process manifests as a 60% reduction in tumor sphere formation capacity and significant suppression of stemness gene SRY-box transcription factor 2 expression [126].
Core roles of oncogenic signaling pathways in lysosomal regulation in CRC
Multiple key oncogenic signaling pathways target core lysosomal molecules to regulate cell fate determination in CRC development and progression, forming complex regulatory networks. These pathways influence lysosomal function through diverse molecular mechanisms, subsequently modulating tumor cell proliferation, survival, and metabolic activities [121, 127]. Table 3 summarizes the mechanisms of action and clinical significance of major signaling pathways in lysosomal regulation.
Bidirectional regulatory role of lysosomes in the tumor immune microenvironment and their therapeutic potential
Lysosomes exert pivotal bidirectional regulatory functions within the tumor immune microenvironment through modulation of antigen presentation and immune checkpoint molecule stability. This dual regulatory capacity positions lysosomes as critical mediators of immune surveillance and tumor immune evasion mechanisms. The lysosomal compartment plays an indispensable role in optimizing antigen presentation efficiency through sophisticated proteolytic processing mechanisms. Within dendritic cells (DCs), the lysosomal protease cathepsin S specifically degrades antigen precursors, substantially enhancing MHC class I molecule antigen presentation efficiency [128, 129]. This process represents a fundamental mechanism by which professional antigen-presenting cells maintain immune surveillance capability against transformed cells. Recent investigations have elucidated a novel therapeutic approach involving the antifungal agent clotrimazole, which modulates DC lactate metabolism through hexokinase 2 inhibition. This intervention enhances lysosomal acidification and increases cathepsin S activity, resulting in a remarkable 40% improvement in cross-presentation efficiency of the model antigen ovalbumin. When combined with anti-programmed cell death-1 (PD-1) antibody therapy, this strategy demonstrates significant anti-tumor efficacy. The effectiveness was evaluated in Mouse Colon 38 transplantation models. Combination treatment groups showed impressive results, achieving 72% tumor volume reduction compared to monotherapy controls. These findings indicate substantial synergistic effects between the two therapeutic approaches [130].
Breakthrough advances in targeting microsatellite instability-high CRC have revealed the therapeutic potential of lysosome-mediated immune checkpoint regulation. Investigators have engineered a synthetic IgP β protein featuring a unique pH-responsive domain that specifically recognizes and binds programmed death-ligand 1 (PD-L1) molecules. This innovative approach promotes PD-L1 lysosomal degradation through the CMA pathway, offering distinct advantages over conventional antibody blockade strategies [131]. The therapeutic efficacy of this approach is demonstrated by substantial enhancement of anti-tumor immune responses. Treatment results in a 2.3-fold increase in interferon-gamma secretion by tumor-infiltrating CD8-positive T cells and a 1.8-fold elevation in granzyme B expression levels [131]. These findings not only illuminate the unique advantages of lysosomal degradation pathways in overcoming immunotherapy resistance but also provide crucial insights for developing next-generation immunotherapeutic agents.
Lysosome-targeted therapy for CRC
The disruption of autophagolysosomal fusion has proven effective in overcoming chemotherapy resistance. Chloroquine (CQ) represents a prototypical agent that inhibits lysosomal acid phosphatase activity, effectively blocking autophagosome-lysosome fusion and leading to aberrant accumulation of the autophagy substrate p62. This mechanism triggers ER stress and significantly enhances chemotherapeutic cytotoxicity [132]. In 5-fluorouracil (5-FU) resistant HCT116/5-FU cell models, combination therapy with CQ reduced the IC50 value of 5-FU from 85.7 μM to 22.3 μM, accompanied by enhanced caspase-3 activation and a 40% reduction in clonogenic capacity [133, 134]. Similarly, the v-ATPase inhibitor bafilomycin A1 inhibits lysosomal acidification, inducing lipidated LC3 aggregation and lysosomal swelling. When combined with oxaliplatin, this approach synergistically promotes ferroptosis in CRC cells, evidenced by a three-fold increase in the lipid peroxidation marker malondialdehyde and 50% downregulation of glutathione peroxidase 4 protein expression [135]. Furthermore, cathepsin inhibitors offer another therapeutic avenue through targeted enzyme modulation. The inhibitor E64d covalently binds to the cysteine residue within the cathepsin B active site, effectively blocking lysosome-mediated extracellular matrix degradation pathways. In colon tumor 26 hepatic metastasis models, E64d treatment reduced liver metastatic nodules by 62% compared to controls, with mechanisms involving matrix metalloproteinase-9 activity inhibition and enhanced lysosomal degradation of the epithelial-mesenchymal transition regulatory factor twist family bHLH transcription factor 1 [136].
The therapeutic potential of natural compounds lies in their ability to provide multi-target lysosomal regulation with potentially reduced toxicity profiles compared to synthetic agents. Periplocin, derived from traditional Chinese medicine, demonstrates this principle through specific Galectin-3 protein binding and inhibition of ubiquitination-mediated degradation. This mechanism promotes excessive lysosomal autophagy, achieving 58% tumor inhibition in SW480 xenografts with accompanying 2.5-fold increases in autophagolysosomes and 35% reduction in proliferating cells [125]. Curcumin operates through complementary mechanisms, disrupting lysosomal membrane integrity via hydrophobic insertion into lipid bilayers. This approach triggers two key cellular events: cathepsin B cytoplasmic release and caspase cascade activation. Meanwhile, transcriptomic analysis reveals important gene expression changes. Specifically, it shows coordinated downregulation of lysosomal genes alongside upregulation of ER stress markers. These transcriptomic findings indicate involvement of lysosome-ER interaction networks in the therapeutic response [137].
The evolution toward precision medicine has driven the development of sophisticated nanodelivery systems that exploit lysosomal biology for enhanced therapeutic outcomes [138,139,140]. Epidermal growth factor-modified hollow mesoporous silica nanoparticles represent this advancement, specifically targeting epidermal growth factor receptor-overexpressing resistant cells through receptor-mediated endocytosis followed by lysosomal escape peptide-mediated drug release. This approach achieves 3.7-fold increases in intracellular drug concentration while circumventing lysosomal degradation pathways, ultimately reversing 5-FU resistance and increasing apoptosis rates from 15 to 45% through coordinated cell cycle arrest and caspase activation [141]. Zinc-phthalocyanine-loaded poloxamine micelles accumulate within CT26 cell lysosomes and generate reactive oxygen species upon 633 nm light exposure, triggering LMP and reshaping tumor energy metabolism. Metabolomic analysis reveals important metabolic changes induced by this treatment. The treatment specifically inhibits expression of key glycolytic enzymes, including hexokinase 2 and pyruvate kinase M2. This inhibition forces cells to undergo metabolic reprogramming toward oxidative phosphorylation. The metabolic shift synergistically contributes to cell death induction [142].
Conclusion
Cancer treatment has undergone remarkable transformation over the past century. We have evolved from early surgical and radiation interventions to sophisticated molecular targeted therapies. This journey from broad-spectrum cytotoxic drugs to precision medicine has opened new possibilities for targeting previously overlooked cellular mechanisms [143]. In recent years, research perspectives on cancer treatment strategies have gradually expanded. The scientific community increasingly focuses on an important question: should we concentrate on directly targeting cancer cells themselves, or achieve therapeutic breakthroughs by regulating the tumor microenvironment [144]. In the current context, lysosome-targeting approaches offer distinct advantages because they can affect both cancer cells and stromal components [145]. The lysosomal dysfunction observed in cancer cells creates cell-autonomous vulnerabilities. Meanwhile, the release of lysosomal contents can regulate immune cell function and stromal cell behavior within the tumor microenvironment. Given the limitations of approaches that focus solely on tumor cells, this dual-targeting capability may hold greater therapeutic potential.
Initial lysosome-targeting therapies primarily focused on utilizing lysosomes as intracellular drug reservoirs. These approaches involved designing nanoparticles that release drugs in the acidic lysosomal environment to overcome tumor cell resistance [146]. Such strategies demonstrated effectiveness by enhancing intracellular drug concentrations and reversing drug resistance. However, their mechanisms of action remained largely limited to the cell-autonomous level, failing to directly address the critical bottleneck of immunosuppressive tumor microenvironments. Subsequently, researchers recognized that lysosome targeting involves not only direct drug delivery but also immunomodulatory strategies. They discovered that clotrimazole can enhance lysosomal acidification and cathepsin S activity by modulating the lactate-lysosome axis. This significantly improves cross-presentation efficiency and dramatically reduces tumor volume when combined with anti-PD-1 therapy [130]. Nevertheless, such approaches primarily target immune cell dysfunction and have limited impact on intrinsic drug resistance mechanisms within tumor cells. The latest breakthrough lies in developing dual-functional strategies that can simultaneously target tumor cells and modulate immune responses. Researchers developed a prion-like chemical inducer of proximity that contains a designed chiral peptide capable of specifically binding PD-L1. It exploits the upregulated CMA activity in melanoma cells to promote PD-L1 degradation, achieving dual effects of counteracting adaptive immune resistance and restoring anti-tumor immunity [147]. This CMA reprogramming strategy represents not only technical advancement but also marks a fundamental shift toward precision medicine. It effectively circumvents the key limitation of compensatory resistance mechanisms that tumors develop when single pathways are targeted.
Lysosomal dysfunction serves not only as the core mechanism driving autophagy-dependent and LDCD, but also participates in complex interactive networks with other regulated cell death pathways. Research demonstrates that lysosomal stress responses can trigger alternative death pathways, including ferroptosis, cuproptosis, and disulfidptosis. This multi-pathway convergence property offers new insights for overcoming tumor resistance. In ferroptosis, lysosomal iron homeostasis regulation plays a crucial role. The case of metformin inducing melanoma ferroptosis through the activating transcription factor 3/nuclear factor erythroid 2–related factor 2 axis aligns with findings that dichloroacetic acid triggers ferroptosis in CRC stem cells through lysosomal iron chelation [148]. Both mechanisms show glutathione depletion and lipid peroxide accumulation. Cuproptosis reveals the connection between lysosomes and metal metabolism [149]. Pan-cancer analysis shows that cuproptosis-related genes exhibit tissue-specific expression patterns [150], particularly demonstrating significant sensitivity in clear cell renal cell carcinoma [151]. The characteristic genes are also associated with immune infiltration, suggesting their potential as predictive biomarkers for immunotherapy response. The newly discovered disulfidptosis further expands this network of programmed cell death mechanisms. Disulfidptosis represents a distinct form of cell death mediated by aberrant intracellular disulfide accumulation in solute carrier family 7 member 11 (SLC7A11)-high cells under glucose starvation conditions. This cell death pathway is triggered by the susceptibility of the actin cytoskeleton to disulfide stress, leading to F-actin collapse in a SLC7A11-dependent manner. Importantly, approximately half of the disulfidptosis-related cell death proteins are associated with epithelial–mesenchymal transition activation, suggesting a critical role in cancer invasion and metastasis beyond cell death induction [152]. These findings suggest that targeting lysosomal function may activate multiple cell death programs simultaneously, including apoptosis, ferroptosis, cuproptosis, and disulfidptosis. This multi-pathway activation could potentially overcome resistance mechanisms that cancer cells develop against single pathway inhibition, as each mechanism targets different cellular vulnerabilities while sharing some common upstream regulators. However, the distinct molecular triggers and execution mechanisms of each pathway provide opportunities for selective therapeutic targeting based on cancer-specific genetic alterations and microenvironmental conditions.
Despite the tremendous potential of lysosome-targeting therapies, numerous controversies and limitations in current research require in-depth exploration. The primary controversy lies in autophagy’s dual functionality. In early tumor stages, autophagy may exert tumor-suppressive effects by maintaining genomic stability and inhibiting inflammatory responses. However, in advanced stages, it may promote cancer cell survival and metastasis [153, 154]. This functional duality makes determining optimal intervention timing extremely complex. Currently, reliable biomarkers to accurately assess which stage of lysosome dependency tumors are in remain lacking. More concerning, recent studies show that autophagy inhibition may enrich highly invasive cells that exhibit stronger metastatic tendencies [155]. Additionally, significant differences exist in lysosomal enzyme activity, pH values, and autophagic flux across different tissue types [156]. The complex interaction networks between lysosomes and other organelles mean that interventions may trigger cascade reactions, leading to severe organ toxicity in metabolically active tissues. From a clinical translation perspective, current lysosomal modulation trials in CRC primarily focus on safety assessments of hydroxychloroquine combined with chemotherapy. The University of Pennsylvania’s Phase I/II trial evaluated the efficacy of hydroxychloroquine combined with folinic acid, fluorouracil, oxaliplatin, and bevacizumab. Preliminary results showed effective autophagy inhibition but persistent adverse reactions including neutropenia, insomnia, and visual disturbances [157]. Although meta-analyses demonstrate survival benefits from autophagy inhibitor treatment, sample sizes remain limited and most are early-phase trials [158]. Furthermore, chloroquine-based drugs have limited membrane permeability in acidic tumor microenvironments and may cause serious toxic reactions such as visual disturbances and electrocardiographic changes at high doses [159]. Most current lysosome-targeting drugs lack high specificity, making it difficult to selectively target specific types of autophagy or distinguish them from other cellular pathways [160]. These limitations collectively emphasize the need for more cautious and comprehensive research approaches in advancing the clinical translation of lysosome-targeting therapies.
As our understanding of tumor biology deepens, future cancer treatment will increasingly focus on personalized and precision strategies, particularly targeting the tumor immune microenvironment and its molecular mechanisms [161]. In this context, the “lysosomal addiction” phenomenon exhibited by cancer cells provides a highly promising target for precision medicine. This unique metabolic dependency creates an exploitable therapeutic window between cancer cells and normal cells, potentially achieving more selective anti-cancer effects while reducing toxicity to normal tissues. The enhanced autophagy-lysosomal flux and upregulation of lysosome-related genes observed in many cancers represent key molecular features that can guide treatment selection. A critical driving force supporting this precision trend is the rapid development of omics-based technologies. These technologies provide powerful tools for revealing the molecular basis of cancer, enabling early detection, optimizing prognostic assessment, and evaluating treatment responses [162]. Advances in molecular profiling technologies allow us to more effectively identify patient subgroups most likely to benefit from lysosome-targeting interventions, truly moving beyond traditional “one-size-fits-all” approaches [163]. Furthermore, integrating artificial intelligence (AI) into clinical decision-making processes holds promise for significantly enhancing our ability to predict patient responses to lysosomal addiction-targeting therapies. AI can integrate complex omics data and clinical information to optimize treatment selection [164]. The ultimate goal is to maximize therapeutic efficacy while minimizing unnecessary toxicity to the greatest extent possible.
In conclusion, these emerging therapeutic approaches offer significant potential for cancer treatment, with lysosomal addiction-based therapies potentially becoming integral components of personalized medical strategies. By combining lysosome-targeting strategies with emerging cell death pathways, new possibilities are opened for overcoming therapeutic resistance and improving patient outcomes. However, their successful clinical translation still depends on continued breakthroughs in key areas, including understanding critical pathway interactions, developing reliable biomarkers, and optimizing personalized treatment selection.
Availability of data and materials
No datasets were generated or analysed during the current study.
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This research was funded in part by a grant from the Shandong Province Medical and Health Science and Technology Project (No. 202304011527) and the 2023 Scientific Research Project of Chinese Association of Ethnic Medicine (Nos. 2023ZY099-71, 2023ZY098-47).
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Literature review and data collection were performed by XW and FA. The first draft of the review was written by XW. Figures and tables were generated by TZ and BW. YF and LY participated in editing the draft and tables. WH participated in editing the draft. BW participated in editing the draft. CJ and WC contributed to the draft editing and language improvement. All authors approved the final manuscript.
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Wang, X., An, F., Wang, B. et al. From “lysosomal addiction” to targeted therapies: exploiting novel windows in colorectal cancer. Eur J Med Res 30, 957 (2025). https://doi.org/10.1186/s40001-025-03145-7
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DOI: https://doi.org/10.1186/s40001-025-03145-7