Spatially organized regulated cell death-immune coupling in solid tumors: integrating spatial omics with actionable regulated cell death biology

Abstract

The therapeutic efficacy of immune checkpoint blockade is frequently compromised by the profound spatial heterogeneity of solid tumors, where distinct ecological niches are associated with different patterns of immune engagement. Spatial omics has substantially refined our understanding of tumor immune topographies. These range from immune-excluded hypoxic and necrotic cores to immune-infiltrated margins enriched with tertiary lymphoid structures (TLS). However, the mechanistic contribution of regulated cell death (RCD) to these spatial domains remains largely unexplored. In this review, we propose the concept of spatially organized RCD-immune coupling as a hypothesis-generating framework. We argue that RCD modalities are not uniformly distributed across tumors, but are influenced by regional microenvironmental constraints, including metabolic zonation, hypoxia, and mechanical stress. Synthesizing emerging evidence, we discuss how apoptosis, necroptosis, pyroptosis, ferroptosis, and PANoptosis may be enriched within distinct tumor niches. We further examine how region-specific release of damage-associated molecular patterns (DAMPs), cytokines, and lipid mediators may be associated with local immune activation, exhaustion, or exclusion. Importantly, we distinguish spatial association from functional causality and emphasize the need for phenotypic validation and perturbation-based studies. This framework positions RCD as a spatially organized component of tumor immune ecology and a basis for future biomarker and therapeutic studies.