A tumor Microenvironment-Derived Prognostic Model Guides IL-27 as a Therapeutic Strategy to Restore T Cell Immunity...

Lung adenocarcinoma (LUAD) exhibits substantial heterogeneity in tumor immune microenvironment (TIME) composition, shaping disease progression and therapeutic response. Here, we integrated transcriptomic and clinical data from TCGA-LUAD to develop a TIME-associated prognostic model. LASSO Cox regression identified eight key genes-S100P, CPLX2, CD200R1, LINC01857, CLEC7A, CLEC17A, COL6A5, and CX3CR1- that yielded a risk score separating patients into two groups with distinct immune states. High-risk tumors were characterized by diminished CD4⁺ Th1 and CD8⁺ T cell infiltration, expansion of M2 macrophages, and cytokine profiles consistent with immune suppression, whereas low-risk tumors displayed immune-active features, including elevated IL-27 signaling. Single-cell RNA sequencing of a murine LUAD model revealed that early tumors featured a T cell-enriched microenvironment with elevated IL-27 signaling, whereas late tumors acquired a macrophage-driven immunosuppressive landscape. Interstitial macrophages acquired an M2-like phenotype, upregulated PD-L1, and suppressed CD4⁺ and CD8⁺ T cell activity through the CD86-CTLA4 and SELPLG-SELL axes. Functionally, IL-27 blockade accelerated tumor growth, whereas recombinant IL-27 restrained tumor progression and enhanced PD-L1/CTLA-4 blockade efficacy by augmenting Th1 and cytotoxic T cell responses. These findings define a TME-based prognostic classifier and position IL-27 as a stage-dependent therapeutic target that restores T cell immunity and boosts checkpoint blockade efficacy.