Complement component C1q is a marker of a particular subpopulation of tissue-resident macrophages and tumor-associated macrophages (TAM), often expressing CD206, HLA-DR, SEPP1, FOLR2, APOE but not SPP1, as revealed by single-cell RNA sequencing (scRNA-seq) in different normal tissues and tumor types. In cancer, the presence of C1q+ TAM often correlates with poor prognosis. Presence of C1q+ TAM correlates with T cell exhaustion in cancer and immune tolerance induction in healthy tissue. C1q is the recognition molecule of the classical complement pathway, binding to immune complexes, pentraxins, or other activators in the tumor microenvironment. C1q directly controls macrophage phenotype by interacting with surface receptors. C1q directly controls T cell phenotype through internalization, binding to mitochondria, and regulation of mitochondrial metabolism. C1q is likely a biomarker of a TAM subpopulation and a driver of cancer progression. The omics era made possible the quest for efficient markers for cancer progression and revealed that macrophage populations are much more complex than just the M1/M2 dichotomy. Complement C1q pops up as a marker of a tolerogenic and immunosuppressive macrophage populations in both healthy and tumor tissues, but the specific role of C1q+ tumor-associated macrophages (TAM) is poorly understood. C1q is co-expressed in healthy and tumor macrophages with human leukocyte antigen DR (HLA-DR), Apolipoprotein E (APOE), and mannose receptor C-type 1 (MRC1) (CD206), suggesting a resident origin of this population. TAM expressing C1q correlate with T cell exhaustion and poor prognosis in numerous cancers. Herein, we discuss the plural roles of C1q in these macrophages and how it could drive cancer progression. The omics era made possible the quest for efficient markers for cancer progression and revealed that macrophage populations are much more complex than just the M1/M2 dichotomy. Complement C1q pops up as a marker of a tolerogenic and immunosuppressive macrophage populations in both healthy and tumor tissues, but the specific role of C1q+ tumor-associated macrophages (TAM) is poorly understood. C1q is co-expressed in healthy and tumor macrophages with human leukocyte antigen DR (HLA-DR), Apolipoprotein E (APOE), and mannose receptor C-type 1 (MRC1) (CD206), suggesting a resident origin of this population. TAM expressing C1q correlate with T cell exhaustion and poor prognosis in numerous cancers. Herein, we discuss the plural roles of C1q in these macrophages and how it could drive cancer progression.