Programmed Cell Death in Urological Cancers: Orchestrating the Immune Microenvironment and Immunotherapy

Programmed cell death regulates the tumor immune microenvironment. A comprehensive synthesis of how multiple programmed cell death pathways collectively orchestrate the remodeling of the urological immune landscape is currently lacking. This review summarizes and discusses how diverse programmed cell death modes, including ferroptosis, pyroptosis, autophagy, PANoptosis, necroptosis and cuproptosis, regulate immune evasion or activation in a context-dependent manner. Current preclinical evidence suggests that necroptosis, pyroptosis, and cuproptosis may enhance anti-tumor immunity by facilitating the release of damage-associated molecular patterns and increasing the infiltration of functional CD8⁺ T cells and dendritic cells, thereby potentially improving responses to immunotherapy. At the same time, several programmed cell death pathways display exhibit pronounced context dependence. In renal cell carcinoma, ferroptosis exhibited a functional contradiction: while its induction directly eliminated cancer cells, the resulting lipid peroxidation could simultaneously impair the survival and metabolic fitness of infiltrating immune cells. This dualistic effect necessitated precise, cell-type-specific strategies to ensure that ferroptosis-mediated tumor suppression did not undermine the anti-tumor immune response. Similarly, autophagy in tumor cells facilitated immune evasion via the selective degradation of major histocompatibility complex class I (MHC-I) and stabilizing programmed death-ligand 1, while it also improved the cytotoxic function and cellular longevity of natural killer cells. Consequently, future drug development should consider cell-type-specific modulation to address these contradictory effects across different cells and avoid unintended immunosuppression. Emerging evidence on PANoptosis, which integrates multiple programmed cell death pathways into a synergistic framework, may provide a useful direction for investigating immune therapeutic resistance. Ultimately, targeting the intricate landscape of programmed cell death may inform strategies for improving cancer treatment and urological immunotherapy, but stronger translational evidence is still needed.