Association of FDG PET/CT and immune profiling with pathologic complete response after neoadjuvant immunotherapy in stage II-III non-small cell lung cancer.

BACKGROUND: Neoadjuvant immunotherapy has emerged as a transformative approach for resectable non-small cell lung cancer (NSCLC). Pathologic complete response (pCR) after neoadjuvant therapy serves as a robust surrogate marker for early treatment efficacy and long-term outcomes. However, reliable noninvasive predictors of pCR before surgery remain an unmet clinical need. This study investigated the association between fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) parameters and tumor-infiltrating immune cell subsets in pre-treatment biopsies with pCR in patients with stage II-III NSCLC treated with immune checkpoint inhibitor (ICI)-based neoadjuvant therapy. METHODS: We retrospectively analyzed 13 patients with stage II-III NSCLC who underwent ICI-based neoadjuvant therapy and baseline FDG PET/CT. pCR was assessed in resected surgical specimens. PET/CT parameters, including tumor-to-liver ratio (TLR) and maximum standardized uptake value (SUVmax), were evaluated before and after neoadjuvant treatment. Multiplex immunofluorescence (mIF) was performed on pre-treatment tumor biopsies to quantify tumor-infiltrating immune cell subsets and functional immune markers. RESULTS: Eight patients (62%) achieved pCR. Compared with the non-pCR group, patients with pCR showed significantly lower post-treatment TLR (median 1.51 vs. 2.14, P=0.004) and a greater relative reduction in TLR (median 0.82 vs. 0.58, P=0.004). Pre-treatment biopsies from patients with pCR demonstrated higher infiltration of CD4+ T cells (P=0.04) and increased TIGIT expression on both CD8+ and CD4+ T cells. Pre-treatment TLR positively correlated with CD68+ macrophages and Ki67+ CD8+ T cells, while changes in TLR were significantly associated with TIGIT+ tumor-infiltrating T cells. During follow-up, recurrence occurred in only one patient in the non-pCR group. CONCLUSIONS: Dynamic changes in PET/CT-derived TLR and immune biomarkers from pre-treatment biopsies were associated with pCR following neoadjuvant immunotherapy in stage II-III NSCLC. These findings support the complementary role of metabolic imaging and immune profiling in improving patient selection and perioperative decision-making.