OSMR coordinates a self-perpetuating circuit linking chemoresistance and neutrophil-driven immunosuppression in gastric cancer

TL;DR

This study identifies OSMR as a key driver linking chemotherapy resistance and immune suppression in gastric cancer, offering a new therapeutic target.

Contribution

The study reveals a novel OSMR-driven feedback circuit connecting tumor survival and immune evasion in gastric cancer.

Findings

OSMR upregulation correlates with poor chemotherapy response and reduced CD8+T cell infiltration in gastric cancer patients.

OSMR activates PI3K/AKT signaling to sustain tumor survival and promotes neutrophil-mediated immunosuppression via BMP5 and PD-L1.

Blocking OSMR with vixarelimab synergizes with chemotherapy to overcome resistance and restore anti-tumor immunity in preclinical models.

Abstract

Chemoresistance and immunosuppression present major challenges in gastric cancer (GC) treatment, with their interplay remaining poorly understood. We identify the Oncostatin M receptor (OSMR) as a central regulator coordinating both chemoresistance and neutrophil-mediated immunosuppression. OSMR was significantly upregulated in GC patients, correlating with poor chemotherapy response and reduced CD8+T cell infiltration. Mechanistically, OSMR directly recruits PI3K, amplifying PI3K/AKT signaling to increase cyclin E2 (CCNE2) expression, thereby sustaining tumor cell survival under chemotherapy-induced stress. Crucially, we uncovered a novel immunoregulatory cascade: OSMR drives BMP5 transcriptional activation, orchestrating N2-polarization of tumor-associated neutrophils (TANs) and upregulating PD-L1 expression on TANs, ultimately impairing CD8+T cell cytotoxicity. Dysfunctional CD8+T cells secreted IL31, activating the OSMR pathway in GC cells and thereby forming a self-perpetuating OSMR-BMP5-IL31 feedback circuit that sustains therapeutic resistance. Therapeutically, OSMR neutralization with vixarelimab synergized with fluorouracil to overcome chemoresistance and reinstate anti-tumor immunity in GC preclinical models. Our findings establish OSMR as a molecular linchpin connecting intrinsic tumor survival pathways (PI3K/CCNE2) with extrinsic immunosuppressive reprogramming (BMP5/TANs/CD8+T cells), providing a clinically actionable target to overcome treatment resistance in GC.

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