TNF-⍺-mediated myeloid-instructed CD14(+)CD4(+) T cells are associated with poor survival in lung adenocarcinoma.

The tumor microenvironment is composed of diverse immune populations that can either support anti-tumor immunity or promote tumor progression. Myeloid cells are major drivers of immunosuppression, yet therapies targeting them have shown limited success. To uncover mechanisms underlying myeloid-driven immune suppression, we performed spatial multi-omics analyses of non-small cell lung cancer (NSCLC). Independent of oncogenic driver status, tumors stratify into lymphoid-enriched, myeloid-enriched, and mixed immune-infiltrated subtypes. In tumor and adjacent non-malignant lungs, we identify myeloid-instructed CD14(+)CD4(+) T cells. These cells arise through trogocytosis adopting an atypical phenotype. In lymphoid-enriched tumors, high infiltration of CD14(+)CD4(+) T cells correlates with poor patient survival. Spatial transcriptomics reveal enrichment of tumor necrosis factor alpha (TNF-α) signaling in CD14(+)CD4(+)-T-cell-rich tumors. Functional assays demonstrate that TNF-⍺ enhanced trogocytosis, promoting the formation of CD14(+)CD4(+) T cells. These findings uncover a TNF-⍺-mediated mechanism of immunosuppression in the TME and highlight aberrant myeloid-T cell interactions as contributors to NSCLC progression.