Targeting Lysosomes for Enhanced Anti-Cancer Therapeutics and Immune Response - Review

Sep 22, 2026

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Cancer remains a leading cause of death in Western countries, and standard chemotherapy and radiotherapy often cause severe side effects while reshaping tumor metabolism and the tumor microenvironment. These changes drive therapeutic failure, including drug resistance, immune evasion, and disease progression. Lysosomes are acidic organelles essential for cellular homeostasis and autophagy, which is commonly upregulated in tumors to protect cells and suppress anti-cancer immunity. Because lysosomes regulate endocytosis and autophagic flux, they can be targeted to attenuate autophagy and improve outcomes. This review surveys lysosome modulators, highlighting strategies that enhance immune responses and inhibit tumor growth and metastasis, including safer agents, synergistic combination approaches, and advanced nanoparticle tumor targeting.

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Abstract

Introduction

Lysosome biology and acidic function

Lysosomes as regulators and autophagy hub

Autophagy roles in cancer survival and therapy resistance

Need for monitoring autophagy steps

Figure 1: Modulating enhanced autophagy in cancer via lysosomal targeting

Ivyspring International Publisher InternationalJournal of Biological Sciences 2026; 22(4): 1693-1716. doi: 10.7150/ijbs.127929 Review Targeting Lysosomes for Enhanced Anti-Cancer Therapeutics and Immune Response Michal Stark, Yehuda G. Assaraf􀀍 The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, The Technion-Israel Institute of Technology, Haifa 3200003, Israel. 􀀍 Corresponding author: Yehuda G. Assaraf: [assaraf@technion.ac.il](assaraf@technion.ac.il). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.11.05; Accepted: 2026.01.06; Published: 2026.01.15 Abstract Cancer is a leading cause of death in Western countries. Apart from surgical resection, the primary treatment modalities chemotherapy and radiotherapy inflict serious side effects, and significantly remodel both tumor metabolism and the tumor microenvironment. This consequently compromises treatment efficacy, resulting in multiple drug resistance, immune evasion and cancer progression. Lysosomes are unique acidic intracellular organelles crucial for maintaining cellular health and homeostasis via degradation of cellular waste. Lysosomes are also required for autophagy, a stress-induced catabolic pathway that is important for cell survival. Autophagy is typically enhanced in tumor cells, as it can confer cyto-protection against the deleterious cytotoxic effects of chemotherapy, and suppress anti-cancer immune response. Owing to their acidic nature and their role in endocytosis, lysosomes can be readily targeted and manipulated, thus attenuating the autophagic flux and improving cancer treatment outcome. Herein we focused on various classic and innovative lysosome modulators, their impact on autophagy, the enhancement of immune response, and consequent inhibition of tumor growth and metastasis. We discuss modalities to minimize adverse effects in cancer patients by either utilizing harmless compounds, achieving synergistic activity with combination therapies, or specifically targeting the tumor by using advanced nanoparticle technologies. Keywords: lysosomes, LMP, autophagy, macrophage, immune response Introduction Lysosomes are eukaryotic membrane-bound cellular organelles with an acidic lumen at a pH range of 4.5-5.5 [1–4], containing approximately 60 hydrolytic enzymes [5] displaying optimal activity at acidic pH [6–8] . These hydrolytic enzymes, including proteases, nucleases, lipases, glycosidases, phospholipases, phosphatases, and sulfatases, are responsible for the degradation of proteins, nucleic acids, lipids, glycosides, and cellular debris, including damaged organelles, thereby maintaining cellular health and homeostasis [9–12] . Apart from their major degradative role, lysosomes are central sensory hubs which respond to multiple cues to regulate metabolism, cell differentiation and division, as well as apoptosis and tumorigenesis [13–16] . Furthermore, lysosomes are key components and regulators of the homeostatic autophagy process [17–19] . The latter involves the sequestration of damaged organelles, misfolded proteins, intracellular pathogens and other foreign substances in double-membrane vesicles known as autophagosomes, which fuse with lysosomes for cargo degradation and recycling (Figure 1) [20–22] . Autophagy promotes either cell survival or cell death [23–27] . As a stress-induced catabolic pathway, autophagy facilitates the adaptation of cells to stress conditions such as starvation, by breaking down damaged or non-essential cellular structures and macromolecules to provide essential metabolites [28,29] . Mitochondrial damage triggers mitophagy (mitochondrial autophagy), by which it protects the cell against release of pro-apoptotic p

FAQs

Why are lysosomes considered promising targets in cancer therapy?

Lysosomes are acidic organelles required for cellular degradation and for autophagy. Their role in regulating autophagic flux makes them accessible for modulation, which can weaken tumor-protective autophagy and improve treatment outcomes.

How does autophagy influence cancer progression and therapy response?

Autophagy can promote tumor cell survival under stress by providing nutrients through degradation. It also supports resistance mechanisms, including protection against DNA damage and enhanced DNA damage repair during treatments such as chemotherapy and radiation.

What strategies are discussed to enhance anti-cancer therapeutics using lysosome modulation?

The review focuses on classic and innovative lysosome modulators, aiming to attenuate autophagy, enhance immune response, and inhibit tumor growth and metastasis. It also discusses approaches such as harmless compounds, synergistic effects in combination therapies, and nanoparticle technologies for tumor-specific targeting.

Sep 22, 2026

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