Exploring regulated cell death in renal cell carcinoma: mechanistic insights and therapeutic perspectives

Renal cell carcinoma (RCC) is the third most prevalent urological malignancy, characterized by histological heterogeneity and complex molecular landscapes. Although established regimens, including surgical intervention, targeted therapies and immunotherapy, effectively manage early-stage disease, patients with advanced RCC still have a poor prognosis. The expanding spectrum of regulated cell death (RCD), ranging from established apoptosis and ferroptosis to emerging modalities like cuproptosis, disulfidptosis and ammonia-induced cell death, offers novel mechanistic insights into tumor vulnerabilities. This tumor progression and subsequent therapeutic resistance are substantially mediated by dysregulated networks of RCD. To systematically deconstruct this mechanistic complexity, this review stratifies RCD into three specific functional dimensions: precise protein signaling, intracellular homeostasis dysregulation, and physiological dysfunction. Because RCC intrinsically evades cascade-governed pathways such as apoptosis to survive immune elimination, its inherent metabolic reprogramming concomitantly creates paradoxical vulnerabilities. Consequently, these tumors exhibit profound susceptibility to homeostasis-disrupting modalities like ferroptosis, cuproptosis, disulfidptosis, and ammonia-induced cell death. Extending this mechanistic framework beyond clear cell RCC (ccRCC), we define the unique metabolic and redox dependencies of underrepresented non-clear cell variants, including papillary RCC (pRCC), chromophobe RCC (chRCC), fumarate hydratase (FH)-deficient RCC and TFE3-rearranged RCC. By evaluating current RCD-targeted pharmacological interventions, this review highlights critical opportunities to exploit these functional dependencies, offering rational approaches to overcome intrinsic resistance and complement existing therapies. Ultimately, integrating this multidimensional RCD framework with multi-omics profiling facilitates a deeper biological understanding of renal tumors and provides a necessary foundation to accelerate the development of precision oncology.