Myeloid Phagocyte Activation by Commensal-Activated Complement C5aR1 Signaling: Implications for Tumor-Directed Lymphocyte Response

The complement peptide C5a, traditionally considered a liver-derived serum protein, is now recognized to be locally produced and activated within the tumor microenvironment. Our data and others' show that epi- thelial and myeloid cells harbor intracellular C5 stores that can be induced and activated by microbial signals – particularly relevant at the gastrointestinal (GI) mucosa. Fusobacterium nucleatum and Candida albicans, two microbes enriched in colorectal cancer (CRC), are known to promote tumor progression by enhancing myeloid infiltration, dampening anti-tumor T-cell responses, and fueling inflammation. However, how these microbes interface with C5aR1 signaling to shape the CRC tumor microenvironment remains unclear. Our preliminary data show that C. albicans and bacterial LPS boost intracellular C5/C5a production in human monocytes and CRC cells. Spatial and single-cell transcriptomics of human CRC tumors reveal increased complement activation, C5aR1 expression, and macrophage infiltration – suggesting a central role for C5aR1 in modulating tumor immunity. Moreover, the ability of C. albicans and F. nucleatum to co-aggregate suggests potential synergy in driving C5aR1-mediated effects. We hypothesize that C5aR1 promotes tumor progression by orchestrating a myeloid-driven, inflammatory and immunosuppressive tumor microenviron- ment, potentiated by complement-inductive signals from CRC-enriched microbes such as Candida albicans and Fusobacterium nucleatum. To test this hypothesis, we will (Aim 1) assess the independent and syner- gistic effects of C. albicans and F. nucleatum on C5aR1-dependent tumor progression, and (Aim 2) define the roles of macrophage- and epithelial-intrinsic C5aR1 signaling. By uncovering how tumor-associated mi- crobes amplify C5aR1 signaling, this work will inform novel strategies for microbe-informed, complement- targeted CRC therapies. Project Number: 1R21CA293616-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jigarkumar Desai | Institution: HACKENSACK UNIVERSITY MEDICAL CENTER, HACKENSACK, NJ | Award Amount: $467,261 | Activity Code: R21 | Study Section: Cancer Prevention Study Section[CPSS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11310532