MUC16 drives macrophage-mediated immunosuppression in pancreatic cancer.

Authors

Christabelle Rajesh, Satish Sagar, Ying Huang, Clara S Mundry, Vijender Chaitankar, Osama Shiraz Shah, Charitha Sumeet, Thomas Caffrey, Kelly A O'Connell, Benjamin Swanson, Fang Yu, Richard R Behringer, Abeesh Prathapan, Michael A Hollingsworth, Prakash Radhakrishnan

Published in

Cancer letters. Pages 218927. Oct 26, 2026. Epub Oct 26, 2026.

Abstract

Mucin-16 (MUC16) is overexpressed in >60% of pancreatic ductal adenocarcinoma (PDAC) cases and correlates with poor outcomes, yet its role in regulating tumor-immune interactions remains incompletely defined. Using KPC and KPC-MUC16 knockout (KPC-MUC16^KO) genetically engineered and orthotopic mouse models, we show that loss of MUC16 markedly reduces tumor burden and reprograms the tumor microenvironment (TME) toward a less immunosuppressive state. MUC16 deficiency significantly decreased CD206⁺ and Ym1/2⁺ M2-like macrophages, increased the M1/M2 ratio, and improved survival. Cytokine profiling identified CCL2 and Serpin-E1 as MUC16- dependent secreted factors that promote macrophage recruitment and polarization; neutralization of these cytokines reduced macrophage migration in vitro. Bone marrow-derived macrophages (BMDM) exposed to MUC16-expressing tumor cells or conditioned media adopted a CD206⁺Arg1⁺ M2-like phenotype, whereas MUC16^KO tumor signals favored inflammatory CD86⁺iNOS⁺ M1-like polarization. Macrophage depletion using clodronate liposomes significantly impaired tumor growth in MUC16-competent tumors but had minimal effect in KPC-MUC16^KO tumors, indicating dependence on macrophage-mediated immunosuppression in the former group. Spatial transcriptomics revealed a globally distinct TME in MUC16^KO tumors, including enhanced antigen-presentation programs, increased complement activation, and fibroblast states skewed toward pro-inflammatory signaling. These findings establish MUC16 as a key orchestrator of macrophage-driven immunosuppression in PDAC and support therapeutic strategies combining MUC16-targeted interventions with TME-reprogramming approaches.

PMID:
42933591
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.

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