Pan-cancer macrophage atlas uncovers that MHC-IIhigh TAMs induce Treg activation through physical interactions

Dendritic cells (DCs) are recognized as the primary antigen-presenting cells (APCs) within the tumor microenvironment (TME), orchestrating T cell responses via the major histocompatibility complex class II (MHC-II). However, the contribution of tumor-associated macrophages (TAMs) to antigen presentation within the TME remains largely unexplored. By integrating single-cell RNA-seq data from 10 cancer types, we discover that tumor-enriched TAMs universally exhibit elevated phagocytosis and MHC-II-mediated antigen presentation, distinct from canonical tumor-promoting M2 macrophages. Notably, MHC-IIhigh TAMs preferentially interact with regulatory T cells (Tregs) across cancers. Using a mouse model of lung adenocarcinoma, we demonstrate that MHC-IIhigh TAMs promote Treg activation and expansion through antigen presentation and direct contact, while their depletion restrains Treg activation and suppresses tumor growth. Moreover, clinical datasets from patients receiving immunotherapy reveal that the presence of MHC-IIhigh TAMs correlates with immunotherapy resistance. Together, these findings redefine macrophage antigen presentation in the TME and reveal new therapeutic opportunities.