Spatial and Temporal Heterogeneity of Macrophage Efferocytosis in Tumors: Emerging Implications for Immunotherapy Biomarkers and Therapeutic Timing

Abstract

Resistance to immune checkpoint blockade (ICB) remains a major barrier in cancer therapy, reflecting the fact that tumor immunity is governed not only by cell type abundance but also by spatial organization and temporal dynamics within the tumor microenvironment (TME). In this review, we examine macrophage efferocytosis as a biologically and clinically actionable process that conditions immunosuppression or immune activation depending on niche context and treatment timing. The central question is whether apoptotic cell clearance by tumor‐associated macrophages (TAMs) can serve as a biomarker‐relevant regulator of therapeutic response, and more broadly, why conventional TAMs and efferocytosis reviews have been insufficient to explain spatial and temporal heterogeneity. Synthesizing evidence from spatial transcriptomics, single‐cell atlas studies, multiplexed tissue imaging, and in vivo lineage tracing, we show that efferocytic macrophages concentrate in defined microanatomical compartments, including tumor margins, perivascular regions, and therapy‐induced apoptotic zones, where they promote tolerogenic signaling and suppress antigen presentation. However, when efferocytosis is modulated in a delayed or spatially restricted manner, antigen persistence is prolonged and adaptive antitumor immunity is enhanced. Organ‐specific differences in macrophage lineage, stromal architecture, and apoptotic burden further shape the functional meaning of efferocytosis across tumor types. On this basis, we propose a working model of efferocytosis‐associated “hotspots” and “deserts” that may support biomarker‐driven patient stratification: these spatial patterns are conceptualized as a model proposed in this review rather than a settled biological category. Overall, this work reframes macrophage efferocytosis as a spatially and temporally constrained determinant of immune contexture with important implications for precision immunotherapy, combination design, and trial optimization.