Lysosomal Rewiring Perpetuates Tumor Immune Evasion in Cancer

ABSTRACT 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 Ca 2+ 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.