Association of FDG PET/CT and immune profiling with pathologic complete response after neoadjuvant immunotherapy in stage II–III NSCLC

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 positron emission tomography/computed tomography (FDG PET/CT) parameters and tumor-infiltrating immune cell subsets in pretreatment 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 was performed on pretreatment 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). Pretreatment biopsies from patients with pCR demonstrated higher infiltration of CD4⁺ T cells (p=0.038) and increased TIGIT expression on both CD8⁺ and CD4⁺ T cells. Pretreatment 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 pretreatment 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.