SPP1-IL10 Axis as Novel Immunotherapeutic Target in Gastric Peritoneal Carcinomatosis

Gastric cancer is 3rd leading cause of cancer-related mortality worldwide. The peritoneum is the most common site of metastasis, accounting for 60% of recurrences. Peritoneal carcinomatosis results in 65% of gastric cancer-associated deaths, resulting in a median overall survival of 6-9 months. Therefore, identifying novel therapies remains a clinically unmet need. SPP1 (osteopontin) is a glycoprotein involved in diverse biological functions. It is secreted by benign and malignant cells. Its role in gastric carcinomatosis is not well defined. Utilizing publicly available transcriptomic datasets, we show that SPP1 is overexpressed in gastric peritoneal metastasis and malignant ascites. Bulk and single-cell analysis demonstrated that SPP1 expression positively correlated with macrophage infiltration in the tumor microenvironment. SPP1 mutant tumors were enriched for macrophage-excluded phenotype. In conjunction with the human data, cytokine array analysis identified elevated SPP1 secretion by murine gastric tumor cells. Recombinant SPP1 promoted macrophage migration and inhibited the secretion of IL-10 in-vitro. Intercellular signaling networks from single-cell sequencing data sets of human malignant ascites revealed SPP1+ epithelial cells regulate macrophage expression of IL-10. Using syngeneic murine models of gastric peritoneal carcinomatosis, we observed that targeted SPP1 blockade diminished tumor growth as demonstrated by a 50% decrease in tumor weight and number of peritoneal nodules. In addition, in-vivo macrophage trafficking and secretion of IL-10 were inhibited by SPP1 blockade. In summary, we have uncovered a novel mechanism of cancer-macrophage crosstalk, suggesting that targeting SPP1 may be effective for reprogramming of the tumor microenvironment in gastric peritoneal carcinomatosis Citation Format: Turcios Lilia, Neelima Hosamani, Ellen Beswick, Joseph Kim, Mautin Barry-Hundeyin. Multi-omic analysis nominates SPP1-IL10 axis as a novel immunotherapeutic target in gastric peritoneal carcinomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7008.