Tumor-Derived SPP1 Drives Immunosuppressive Macrophage Reprogramming in Gastric Peritoneal Carcinomatosis

Turcios, L.; Hosamani, N.; Beswick, E.; Ubil, E.; Carey, M.; Leinwand, J.; Nomura, S.; Yan, J.; Evers, M.; Kim, J.; BARRY-HUNDEYIN, M.

doi:10.64898/2026.06.21.733605

bioRxiv · 10.64898/2026.06.21.733605

Tumor-Derived SPP1 Drives Immunosuppressive Macrophage Reprogramming in Gastric Peritoneal Carcinomatosis

Turcios, L.·Hosamani, N.·Beswick, E.·Ubil, E.·Carey, M.·Leinwand, J.·Nomura, S.·Yan, J.·Evers, M.·Kim, J.·BARRY-HUNDEYIN, M.

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Abstract

Peritoneal carcinomatosis is a major cause of death in gastric cancer, yet effective therapies remain limited. Tumor-derived soluble factors are increasingly recognized as key regulators of the peritumoral microenvironment. Here, we nominate osteopontin (SPP1) as a tumor-derived mediator that orchestrates macrophage-driven immunoregulation in gastric peritoneal carcinomatosis. Using integrated analyses of human clinical datasets and murine models, we demonstrate that tumor-secreted SPP1 promotes macrophage recruitment and induces tolerogenic IL-10 production. Clinically, SPP1 correlated with inferior overall survival and progression-free survival in gastric cancer. In syngeneic murine models of gastric peritoneal carcinomatosis, intracavitary pharmacologic inhibition of SPP1 restricted peritoneal dissemination, impaired macrophage infiltration and suppressed IL-10 production. Consistent with these findings, macrophage depletion phenocopied antitumor effects of SPP1 inhibition, resulting in decreased metastatic burden. Collectively, these findings define a mechanism of tumor-macrophage crosstalk that promotes peritoneal dissemination and provide a rationale for therapeutic targeting of SPP1 in gastric peritoneal carcinomatosis.

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Turcios, L., Hosamani, N., Beswick, E., Ubil, E., Carey, M., Leinwand, J., Nomura, S., Yan, J., Evers, M., Kim, J., BARRY-HUNDEYIN, M.. 2026-06-23. Tumor-Derived SPP1 Drives Immunosuppressive Macrophage Reprogramming in Gastric Peritoneal Carcinomatosis. https://doi.org/10.64898/2026.06.21.733605

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