Circulating cell populations as response predictors and targets to improve immunotherapy in metastatic lung cancer

Immunotherapy efficacy varies among patients with advanced non-small cell lung cancer (NSCLC). Here, we profiled baseline systemic immunity in patients with stage IV NSCLC treated with anti-PD-1 plus chemotherapy to identify immune mechanisms and circulating biomarkers associated with response. We prospectively enrolled 33 treatment-naive patients, including 22 responders and 11 non-responders at week 9, and 17 responders and 16 non-responders at 6 months. Responders showed increased frequencies of circulating T cells expressing CD69, TCF-1, and CXCR3. In contrast, non-responders exhibited higher frequencies of CTLA-4-, CD161-, and IL-10-expressing CD4⁺ and CD8⁺ T cells. These systemic immune profiles were mirrored in the tumor microenvironment in an independent cohort. Importantly, combined CTLA-4 and PD-1 blockade reactivated anti-tumor T cell features in non-responders in vitro, highlighting CTLA-4 as a potential driver of resistance. Together, these findings support personalized immunotherapy strategies guided by systemic immune biomarkers in advanced NSCLC.