Interleukin-9 Receptor Signaling Promotes an Immunosuppressive Tumor Immune Microenvironment in Oncogene-Driven Non-Small Cell Lung Cancer 2264775

Introduction Non-small cell lung cancer (NSCLC), particularly oncogene-driven subtypes, remains a leading cause of cancer-related mortality, underscoring the urgent need for novel immunotherapies that effectively target the tumor immune microenvironment (TIME). The interleukin-9 receptor (IL-9R) signaling pathway is understudied but emerging evidence, including our previous work, suggests a pro-tumoral role in NSCLC by promoting an immunosuppressive TIME. We hypothesize that IL-9R signaling fosters immunosuppression within the lung TIME of NSCLC and that its blockade represents a viable therapeutic strategy to restrain tumor progression. Methods Using a K-rasLSL-G12D/+; p53fl/fl (KP) mouse model of NSCLC, we compared tumor development between IL-9R knockout (Il9r—/—) and wild-type (WT) mice. Flow cytometry was performed to analyze lung-infiltrating immune cell populations. Bone marrow chimera experiments were conducted to assess the contribution of IL-9R signaling in hematopoietic versus non-hematopoietic compartments. Results Il9r—/— tumor-bearing mice exhibited significantly reduced lung tumor burden compared to WT controls. Flow cytometric analysis revealed that IL-9R deficiency decreased the accumulation of immunosuppressive myeloid cells, including neutrophils/granulocytic MDSCs and arginase 1+ macrophages, while enhancing pro-inflammatory cytokine production (IFN-γ, TNF-α, and IL-17) by T cells. Bone marrow chimera studies showed that WTmice reconstituted with Il9r—/— bone marrow exhibited reduced tumor burden, whereas Il9r—/— recipients reconstituted with WTbone marrow displayed tumor progression comparable to WT controls, indicating that IL-9R signaling in hematopoietic cells drives tumor-promoting immunosuppression. Conclusion Our findings identify IL-9R signaling as a critical regulator of the immunosuppressive lung TIME and suggest that targeting the IL-9R pathway may represent a promising immunotherapeutic strategy for oncogene-driven NSCLC.