Influence of neoadjuvant spatially fractionated stereotactic body radiotherapy on antitumor immunity and pathological response to toripalimab-based immunochemotherapy in resectable stage IIA-IIIB non-small cell lung cancer.

8046 Background: Neoadjuvant immunochemotherapy has improved outcomes in resectable non–small cell lung cancer (NSCLC); however, pathological complete response (pCR) rates remain limited, and strategies to further amplify antitumor immunity are needed. Spatially fractionated stereotactic body radiotherapy (SF-SBRT, Lattice) delivers spatially separated high-dose regions "peaks" to promote immunogenic cell death while maintaining low-dose regions "valleys" that preserve the tumor immune microenvironment (TIME). We hypothesized that integrating SF-SBRT with toripalimab-based immunochemotherapy could reprogram the TIME and enhance pathological response in resectable NSCLC. Methods: This prospective phase II study enrolled resectable stage IIA–IIIB NSCLC (NCT06293690). Patients received one fraction of Lattice SF-SBRT (12 Gy peak / <4 Gy valley) on Day 1, followed by toripalimab plus chemotherapy on Day 2, administered every 3 weeks for 2 cycles prior to surgery. The primary endpoint was major pathological response (MPR). Secondary endpoints included pCR, radiological response, nodal downstaging, event-free survival, overall survival, and safety. Single-cell RNA sequencing (scRNA-seq) was performed to characterize treatment-associated immune remodeling. Results: 20 patients completed neoadjuvant therapy and underwent curative-intent resection, R0 resection was achieved in all patients without treatment-related surgical delays. MPR was observed in 95.0% (19/20) of patients, including a pCR rate of 55.0% (11/20). The radiological objective response rate was 100.0%. Nodal downstaging to ypN0 occurred in 82.4% (14/17) of patients with baseline nodal involvement, corresponding to an overall ypN0 rate of 85.0%. Grade 3–4 treatment-related adverse events occurred in 15.0% (3/20), with no grade ≥2 radiation pneumonitis. scRNA-seq revealed enhanced cytotoxic T-cell activation, reduced immunosuppressive myeloid populations, and coordinated immune remodeling following neoadjuvant treatment. Conclusions: Neoadjuvant SF-SBRT combined with toripalimab-based immunochemotherapy was feasible, safe, and achieved high pathological response rates in resectable stage II–III NSCLC. These findings suggest that SF-SBRT may function as an immune-reprogramming strategy that amplifies neoadjuvant immunotherapy efficacy and warrants further validation in randomized clinical trials. Clinical trial information: NCT06293690 . Characteristics No. of Patients (%) Radiological Response (RECIST 1.1) CR 2 (10.0) PR 18 (90.0) Pathological Response Major pathological response (MPR)* 19 (95.0) └ Pathological complete response (pCR) † 11 (55.0) ypN0 ‡ 17 (85.0) * MPR: < 10% residual viable tumor (RVT); † pCR: 0% RVT in primary ‡ ypN0: 14/17 patients with baseline N + achieved downstaging.