<p>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.</p>