Complement component C6 deficiency exacerbates colorectal tumorigenesis by abolishing membrane attack complex...

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, necessitating a deeper understanding of its underlying molecular mechanisms. The complement system, a prominent arsenal of innate immunity, has emerged as a pivotal regulator of tumor immunity, yet its specific role in CRC remains inadequately explored. Herein, we reported that complement C6, an indispensable component of the terminal membrane attack complex (MAC), was markedly reduced in human CRC tissues and lower levels of C6 were associated with poor overall survival (OS) in patients. In an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced murine CRC model, C6 deficiency exacerbated colitis-associated tumorigenesis. Mechanistically, C6 deficiency abolished MAC formation and promoted the survival of malignant transformed colorectal epithelial cells. Moreover, C6 loss also resulted in an increased presence of M2 tumor-associated macrophages (TAMs) and a significant reduction in T and B cell populations. Additionally, the absence of C6 altered the local levels of several critical chemokines and cytokines, including CCL2/MCP-1, CXCL13/BLC, CCL17/TARC, IL-11 and TGF-β1, thereby contributing to the establishment of an immunosuppressive tumor microenvironment. Collectively, our findings indicate that C6 exerts a protective role in CRC initiation by mediating MAC-dependent tumoricidal activity and modulating immune responses, highlighting its potential as a therapeutic target. Notably, pan-cancer analysis further revealed that C6 expression was consistently decreased across multiple cancer types and was strongly correlated with immune modulation.