Engineering lysosomal collapse for cancer therapy: From mechanistic insights to nanotherapeutic innovations

Lysosomes are markedly altered in tumor cells, exhibiting increased number and size, enhanced acidification, elevated cathepsin activity, and remodeled ion channel composition. These adaptations confer heightened degradative capacity and metabolic plasticity, supporting tumor survival, progression, and therapeutic resistance. Beyond their classical catabolic role, lysosomes function as central hubs for nutrient sensing, stress adaptation, and transcriptional regulation, making lysosomal integrity an emerging vulnerability in cancer therapy.

This review aims to elucidate the therapeutic potential of inducing lysosomal collapse as an anticancer strategy, with a particular focus on recent nanotherapeutic approaches designed to precisely disrupt lysosomal function.

This study systematically summarizes current knowledge on lysosomal structure and function in tumor cells and analyzes preclinical studies that exploit lysosomal destabilization for cancer treatment. Nanotherapeutic strategies targeting lysosomes are categorized according to their underlying mechanisms, including gas generation-mediated blasting, osmotic swelling, fiber-induced expansion, oxidative membrane damage, and direct phospholipid bilayer disruption. For each strategy, the design rationale, mechanistic basis, and representative experimental outcomes are critically evaluated.

Accumulating evidence demonstrates that controlled lysosomal membrane permeabilization or rupture can effectively induce tumor cell death, reverse drug resistance, suppress metastasis, and alleviate immune evasion. Nanotherapeutic platforms enable spatially and temporally precise lysosomal disruption, enhancing antitumor efficacy while minimizing off-target toxicity. Comparative analysis reveals distinct advantages and limitations among different lysosome-targeting strategies, underscoring the importance of rational nanomaterial design.

These advances establish lysosomes as central regulators of tumor biology and promising therapeutic "death triggers". Lysosome-targeted nanotherapeutics represent a powerful and versatile approach for overcoming major barriers in cancer treatment, offering new opportunities for precise, effective, and mechanism-driven anticancer interventions.