A tumor Microenvironment‐Derived Prognostic Model Guides IL‐27 as a Therapeutic Strategy to Restore T Cell Immunity in Lung Adenocarcinoma

ABSTRACT 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.