Macrophages in tumors with downregulated MHC-I expression: emerging therapeutic opportunities and translational challenges

Abstract

Tumor-associated macrophages (TAMs) are the dominant component of the tumor microenvironment and exhibit remarkable phenotypic plasticity and heterogeneity that extends beyond the classical M1/M2 polarization, as revealed by single-cell transcriptomics across multiple cancer types. Downregulation of major histocompatibility complex class I (MHC-I) on tumor cells is a common immune evasion strategy that profoundly shapes TAM composition and function. Conversely, TAMs reciprocally modulate tumor MHC-I expression. This review provides an overview of the verified and hypothetical mechanisms of bidirectional regulatory interactions between MHC-I on tumor cells and TAMs. Since these interactions likely differ between tumors with reversible and irreversible MHC-I downregulation, their potential significance in tumor immunotherapy should be assessed separately for each MHC-I reduction mechanism. Bidirectional regulatory interactions between tumor-associated macrophages (TAMs) and major histocompatibility complex class I (MHC-I) molecules on tumor cells shape the tumor microenvironment and immunotherapy responses. MHC-I downregulation alters TAM composition and function, including phagocytosis. Repolarizing TAMs and activating phagocytosis represent promising therapeutic strategies for "cold" tumors with MHC-I deficiency, but translational challenges require distinguishing MHC-I loss mechanisms.