TNF⍰-mediated myeloid-instructed CD14 ⁺ CD4 ⁺ T cells within the tumor microenvironment are associated with poor survival in non-small cell lung cancer

The tumor microenvironment (TME) harbors a diverse array of innate and adaptive immune cells that can either support anti-tumor immunity or facilitate tumor progression. Among these, myeloid cells are key drivers of immunosuppression, yet therapeutic strategies targeting their function have achieved limited clinical success. A deeper understanding of the mechanisms by which immunosuppressive myeloid cells promote tumor progression is needed to guide the development of more effective treatments. Using spatial multi-omics analyses, we identified a population of myeloid-instructed CD14 ⁺ T cells present in both the tumor core and adjacent non-malignant lung tissue of patients with non-small cell lung cancer (NSCLC). CD4 ⁺ T cells acquired CD14 from myeloid cells by trogocytosis, resulting in an atypical T cell phenotype. High infiltration of CD14 ⁺ CD4 ⁺ T cells in the tumor core was associated with poor patient survival. Spatial transcriptomics profiling revealed that tumors enriched in CD14 ⁺ CD4 ⁺ T cells exhibited increased TNF⍰ signaling. Functional assays demonstrated that TNF⍰ enhanced trogocytosis, promoting the transfer of myeloid membrane components to CD4□ T cells and driving the accumulation of CD14□CD4□ T cells. These findings uncover a novel TNF⍰-mediated mechanism of immunosuppression in the TME, whereby TNF⍰ promotes aberrant myeloid–T cell interactions that may contribute to tumor progression. This work highlights a previously unrecognized axis of innate–adaptive immune crosstalk in NSCLC and suggests that targeting TNF⍰ could disrupt this pathway, restore effective T cell function, and improve therapeutic outcomes.