Jul 2026· Biochimica et biophysica acta. Reviews on cancer· Vol 1881, pp.
189669
· 0 citations· 188 references
Medicine
TL;DR
The LSR network is established as a central regulator of cellular homeostasis, thereby emerging as a promising therapeutic target in cancer and other lysosome-associated disorders.
Abstract
Lysosomes are vital organelles that maintain cellular homeostasis and orchestrate dynamic adaptations during physiological and pathological stress. Lysosomal damage, caused by various extrinsic and intrinsic factors, impairs its integrity and simultaneously disrupts the normal functioning of other organelles, including the endoplasmic reticulum and mitochondria. Lysosomal homeostasis through the lysosomal stress response (LSR) network aids cells in adapting to organelle damage, nutrient fluctuations, oxidative stress, and metabolic irregularities. This coordinated network is primarily governed by proteins, including mTOR, TFEB/TFE3, AMPK, Rag GTPases, Ragulator, and TRPML1, which integrates mechanisms involving rapid lysosomal membrane repair, selective elimination of extensively damaged lysosomes, de novo lysosomal biogenesis, and lysosomal reformation pathways. Dysregulation of the LSR network leads to different types of diseases, including cancer. This review summarizes the current understanding of lysosomal damage mitigation, particularly in cancer, where remodeling of the LSR network not only enables cancer cells to maintain metabolic plasticity by resisting therapeutic stress and promoting malignancy but also identifies the LSR network as a critical determinant in tumorigenesis. We further provide a detailed discussion of emerging evidence on the disruption of lysosomal homeostasis, highlighting strong links between lysosome-targeting drugs and cancer therapeutics. Altogether, we establish the LSR network as a central regulator of cellular homeostasis, thereby emerging as a promising therapeutic target in cancer and other lysosome-associated disorders.
Lysosomes are central regulators of cellular homeostasis, integrating catabolic and anabolic reactions to sustain metabolism. In cancer, however, lysosomal function is not merely upregulated but selectively rewired into distinct, context-dependent states that actively drive tumor immune evasion. This review proposes a conceptual framework linking metabolic, oxidative, oncogenic, and inflammatory pressures to six dominant lysosomal rewiring programs. Chronic nutrient deprivation and hypoxia activate AMPK-ULK1 and HIF signaling, promoting TFEB/TFE3-dependent lysosomal biogenesis, hyper-acidification, and autophagosome-lysosome fusion, collectively degrading immune effectors such as IL-1β and MHC complexes and impairing T-cell priming. Disseminated tumor cells exploit TPC2-mediated Ca2+ signaling and GLS1-dependent metabolism to buffer oxidative stress and support metastatic colonization, while dysregulated PI3K-AKT-mTOR and MYC signaling drive lysosomal peripheralization and lysosomal biogenesis through Arl8b-BORC-kinesin complexes, facilitating cathepsin-mediated exocytosis and MHC-I degradation. Chronic inflammation, sustained by tumor-associated macrophages, myeloid-derived suppressor cells, and IL-6/IL-10 gradients, further reinforce immune suppression. Beyond mechanisms, we also assess the translational readiness of the implicated molecular mediators, distinguishing those with established pharmacological outcomes, such as PI3K-AKT-mTOR inhibitors and repurposed chloroquine/hydroxychloroquine, from mediators that remain strictly preclinical, including TPC2, Arl8b-BORC, and CMTM6/DHHC3, or that are currently undruggable, such as TFEB/TFE3. By framing lysosomes as state-specific orchestrators of immune escape rather than uniform stress organelles, this review offers a mechanistic and translational roadmap for developing lysosome-directed strategies to restore anti-tumor immunity.
N. Al‐Hoshani, Asad Ullah, M. Ali et al.· Immunology and Cell Biology· 0 citations
Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains cellular homeostasis by degrading soluble proteins containing KFERQ-like motifs. Although CMA has traditionally been recognized for its role in protein quality control and cellular stress adaptation, increasing evidence shows that it is frequently altered in cancer, where it regulates multiple processes that promote tumor initiation, progression, and therapy resistance. The growing number of identified CMA substrates involved in cell proliferation, apoptosis, metabolism, DNA damage response, immune regulation, inflammation, and cellular plasticity suggests that CMA is much more than a protein degradation pathway; it is an important regulator of tumor adaptation. In this review, we bring together current evidence to provide a comprehensive understanding of how CMA contributes to the Hallmarks of Cancer, including sustained proliferative signaling, resistance to cell death, metabolic reprogramming, invasion and metastasis, immune evasion, and the enabling characteristics of genome instability and tumor-promoting inflammation. We further explore the emerging roles of CMA in cellular plasticity and cancer stem cell maintenance, two interconnected processes that drive tumor progression, metastasis, and therapeutic resistance. By integrating evidence from diverse tumor types, this review provides a comprehensive understanding of how CMA shapes multiple hallmarks of cancer by selectively degrading key regulatory proteins. Finally, we highlight the context-dependent roles of CMA, identify key gaps in our current understanding, and discuss the opportunities and challenges of targeting CMA for cancer therapy. Overall, this hallmark-based perspective provides an integrated understanding of how CMA contributes to multiple hallmarks of cancer and supports its potential as a therapeutic target.
Meenakshi Tiwari, Lokendra Kumar Sharma, Bandana Chakravarti et al.· Frontiers in Oncology· 0 citations
Mitochondria, often referred to as the powerhouses of the cell, play a pivotal role in maintaining cellular homeostasis through the regulation of energy production, redox balance, and apoptosis. Recent evidence highlights the significance of mitochondrial dynamics, fusion, fission, biogenesis, and mitophagy, enabling cells to adapt to changing physiological and environmental conditions. Dysregulation of these dynamic processes alters mitochondrial function, promoting metabolic reprogramming, evasion of apoptosis, and resistance to chemotherapy. Specifically, enhanced mitochondrial fission is often linked to increased metabolic flexibility and resistance to cell death, while aberrant fusion supports mitochondrial quality control under cellular stress. Additionally, tumour cells also exhibit bioenergetic flexibility, dynamically switching between OXPHOS and glycolysis to meet energy demands and overcome therapeutic stress. This metabolic change influences ROS levels, directly affecting the efficacy of anticancer agents in cancer cells. Such adaptations are now recognised as hallmarks of drug-resistant cancers. This review explores the mechanistic interplay between mitochondrial dynamics and cancer bioenergetics, emphasising how these processes contribute to drug resistance. We also focus on emerging therapeutic strategies, particularly smallmolecule inhibitors targeting mitochondrial fusion and fission that offer promising potential to restore chemosensitivity and disrupt cancer cell survival. A deeper understanding of mitochondrial behaviour in cancer may reveal novel therapeutic targets for the development of more effective and durable cancer treatments.
Varsha Johariya, Vaibhav Singh, Rakesh Kore et al.· Mini-Reviews in Medical Chem...· 0 citations
The endo-lysosomal system is a central regulator of intracellular trafficking, cargo degradation, and metabolic homeostasis. Its dynamic function is closely intertwined with lipid metabolism, forming an integrated regulatory network termed the endo-lysosomal–lipid axis. Disruption of this axis can impair endosomal maturation, lysosomal acidification, autophagic degradation, and lysosome-centered signaling pathways, resulting in defective cellular clearance and chronic inflammatory responses. Conversely, dysfunction of the endo-lysosomal system disrupts cholesterol trafficking, lipid redistribution, and macromolecular degradation, ultimately promoting secondary lipid accumulation and metabolic imbalance. In this review, we summarize the reciprocal interactions between lipid metabolism and endo-lysosomal function, with particular emphasis on membrane trafficking, lysosomal homeostasis, autophagy, membrane contact sites, and multicellular lipid clearance networks. We further discuss how these interconnected processes contribute to disease progression and highlight emerging therapeutic strategies aimed at restoring lysosomal function and lipid homeostasis. Understanding the dynamic regulation of the endo-lysosomal–lipid axis may provide new mechanistic insights into metabolic and neurodegenerative disorders and identify novel therapeutic opportunities.
Yao Du, Li Li, Mingtao Du et al.· Frontiers in Cell and Develo...· 0 citations
Lysosomes serve as central degradative hubs in cells, playing critical roles in maintaining protein homeostasis, clearing damaged organelles, and regulating metabolic signaling. Tumor cells heavily rely on lysosomal functions during proliferation, invasion, and drug resistance, a dependency that concurrently endows them with inherent susceptibility to lysosomal membrane permeabilization (LMP). Current cancer therapies rely heavily on surgical resection for early-stage disease, and chemotherapy or radiotherapy for advanced-stage cancers, but these modalities are limited by poor efficacy, severe side effects, and drug resistance. Therefore, targeting LMP to induce lysosome-dependent cell death (LDCD) represents a promising breakthrough. This review systematically summarizes the molecular mechanisms underlying LMP initiation and execution, as well as the regulatory pathways of LDCD modalities, including apoptosis, necroptosis, ferroptosis, pyroptosis, immunogenic cell death, and autophagy-dependent death. It further highlights the dual roles of lysosomes and LDCD in the tumor microenvironment and their core functions in tumor progression. Additionally, we outline classic therapeutic strategies targeting LMP and novel lysosome-targeting technologies, and discuss combination therapy regimens based on lysosomal modulation. These advances provide comprehensive theoretical foundations and new insights for the development of broad-spectrum lysosome centered anticancer drugs.
Yang Li, Jiajie Feng, Xinzhu Dong et al.· Biomarker Research· 0 citations
Autophagy, as a core mechanism for maintaining cellular homeostasis, influences differentiation and functional activation of immune cells by regulating metabolic reprogramming. Crucially, autophagy serves as a molecular switch that precisely modulates differentiation and subsequent cell fate decisions. It achieves this by eliminating intracellular danger signals or key complexes, thereby determining whether immune cells undergo PANoptosis, an inflammatory death mode that integrates features of pyroptosis, apoptosis and necroptosis. The present review systematically discusses the regulatory role of autophagy in the developmental, differentiation and metabolic pathways of various immune cells. Furthermore, it elucidates the mechanistic details by which autophagy, and particularly mitophagy, dampens excessive PANoptosis activation through the elimination of danger signals (such as mitochondrial DNA and reactive oxygen species) or the degradation of PANoptosome components. Additionally, it clarifies the molecular mechanism by which autophagy dysregulation, induced by specific pathological conditions, leads to inflammatory responses and immunopathological damage. Overall, this review establishes the significance of the autophagy-PANoptosis axis in the development and progression of autoimmune diseases and tumors, providing a solid theoretical foundation for the optimization and innovation of therapeutic strategies for these diseases.
Ya-Nan Guo, Xin-Yue Zhou, Yi-Xiao Tian et al.· International Journal of Mol...· 0 citations
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