Complement C1q is a key player in tumor-associated macrophage-mediated CD8⁺ T cell and NK cell dysfunction in malignant pleural effusion

Macrophages play a crucial role in malignant pleural effusion (MPE), a frequent complication of advanced cancer. While C1q⁺ macrophages have been identified as a pro-tumoral cluster, direct evidence supporting the role of C1q-mediated macrophages remains to be elucidated. This study employed global and macrophage-specific knockout mice to investigate the role of C1q in MPE. The data demonstrated that C1q deficiency in macrophages suppressed MPE and prolonged mouse survival. scRNA-seq analysis of the C1qa^-/- mouse MPE model revealed that C1q deficiency significantly decreased the proportion of M2 macrophages in MPE. <i>In vitro</i> experiments suggested that C1q expression was gradually upregulated during M2 polarization, which was C1q-dependent, as was antigen presentation. Deficiency of C1q in macrophages rescued the exhausted status of CD8⁺ T cells and enhanced the immune activity of CD8⁺ T cells and NK cells in both MPE and pleural tumors. Cell-to-cell interaction analysis demonstrated that C1q deficiency attenuated the immunoinhibitory effects of macrophages on NK cells by downregulating the CCR2-CCL2 signaling axis. Metabolomic analysis revealed significantly elevated hippuric acid levels in C1q-deficient mouse MPE. Treatment with either hippuric acid or a CCR2 antagonist inhibited MPE and tumor growth, with an even more pronounced effect observed when both treatments were combined.