Spatial architecture shapes programmed cell death-associated immune niches and therapeutic resistance in clear cell...

Clear cell renal cell carcinoma (ccRCC) is characterized by VHL-HIF pathway alterations, lipid remodeling, abnormal angiogenesis, and marked immune heterogeneity. These features create a highly vascular yet unevenly perfused microenvironment in which vascular dysfunction, hypoxia, stromal barriers, and myeloid clearance influence whether cell death becomes immunologically productive. Although immune checkpoint inhibitor combinations, vascular endothelial growth factor receptor tyrosine kinase inhibitors, and HIF-2α inhibitors have improved outcomes, primary and acquired resistance and discordant responses among lesions remain common. Bulk PD-L1 expression, immune-cell abundance, and cell-death-related transcript signatures do not resolve this heterogeneity. Following current nomenclature, regulated cell death (RCD) is the mechanistically preferred umbrella term; we retain programmed cell death (PCD) in the conceptual label because it remains widely used in the RCC oncology literature, while requiring RCD execution-level evidence for mechanistic claims. Single-cell and spatial multi-omics studies increasingly show that the identity of the dying cell, execution of the death program, accessibility of death-derived material, and the recipient immune cells operate as a coupled local system. We define a PCD-associated immune niche as a spatial tissue state in which representative, non-exclusive immune-routing axes can direct tumor-cell death toward cDC1-mediated cross-presentation and adaptive antitumor immunity, TAM-dominant efferocytosis and tissue repair, or intermediate mixed states. This Review focuses predominantly on ccRCC, evaluates ferroptosis, apoptosis, pyroptosis, necroptosis, and PANoptosis, and briefly considers emerging RCD modalities for which ccRCC evidence is less mature. We further propose composite spatial biomarkers and mechanism-guided combinations that link cellular source, execution evidence, immune routing, and clinical outcome.