| Sumario: | Background: To optimize precision immunotherapy for advanced NSCLC, comprehensive tumor immune microenvironment (TIME) characterization is crucial for efficacy prediction. Methods: Pretreatment tumor samples from 46 advanced NSCLC patients treated with PD-1/PD-L1 inhibitors were analyzed. The subregional abundance and spatial proximity scores of TIME cell subpopulations in 27 samples were assessed via multiplex immunohistochemistry (mIHC) targeting pan-CK, CD163, CD8, FoxP3, PD-1, and PD-L1. Correlations between the TIME features, clinicopathologic factors, treatment response, and prognosis were evaluated. Results: CD8+FoxP3+ cells were identified in NSCLC tissues, predominantly expressing PD-1/PD-L1. The PD-L1 TPS subgroups showed significant immune cell density/proximity differences, but CD8+FoxP3+PD-1+ infiltration was PD-L1 TPS-independent. Responders had higher CD8+FoxP3+PD-1high density (p = 0.0497) and proximity scores (p = 0.0099) than non-responders. The CD8+FoxP3+PD-1+ presence and tumor proximity were essential for favorable outcomes. In low-PD-L1 TPS patients, the CD8+FoxP3+PD-1+ abundance and proximity scores strongly predicted the response (AUC: 0.79 and 0.75 vs. PD-L1 TPS AUC = 0.58). A survival analysis linked the presence and proximity score of CD8+FoxP3+PD-1+ cells to prolonged overall survival (OS) and progression-free survival (PFS). Notably, a low proximity score of CD8+FoxP3+PD-1+ cells emerged as an independent risk factor for a shorter PFS (HR = 6.16, 95% CI: 2.12–17.93, p = 0.001). Conclusion: The CD8+FoxP3+PD-1+ spatial proximity to tumor cells robustly predicts improved immunotherapy outcomes in advanced NSCLC.
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