Background <p>Chemoimmunotherapy outperforms immunotherapy alone in advanced non-small cell lung cancer (NSCLC). However, current anatomical imaging and programmed death-ligand 1 (PD-L1) assessments are insufficient for early response prediction and do not directly capture treatment-induced immune effector function. Whether ⁶⁸Ga-grazytracer PET/CT, which visualizes granzyme B as a marker of CD8⁺ T‑cell effector function, could assess early response and reveal potential differences between intravenous and bronchial arterial infusion (BAI)-based chemoimmunotherapy remains unknown.</p> Methods <p>In this prospective study, 60 patients with advanced NSCLC receiving BAI-based (<i>n</i> = 28) or intravenous (<i>n</i> = 32) chemoimmunotherapy underwent ⁶⁸Ga-grazytracer PET/CT after 1–2 treatment cycles. The primary endpoint was a 6-month objective response (iRECIST). Secondary endpoints compared immune activation between groups and the performance of ⁶⁸Ga-grazytracer PET/CT for early response assessment versus conventional biomarkers (baseline tumor size [SLD], early anatomical change [ΔSLD], and PD-L1 expression). Statistical analyses included ROC curve analysis, logistic regression, and bootstrap internal validation.</p> Results <p>BAI-based chemoimmunotherapy showed higher ⁶⁸Ga-grazytracer uptake (maximum standardized uptake value [SUV_max]: 2.86 ± 0.71 vs. 2.19 ± 0.80, <i>P</i> = 0.001) and objective response rate (60.71% vs. 34.38%, <i>P</i> = 0.04) than intravenous chemoimmunotherapy, suggesting a possible association with enhanced immune activation. The SUV_max demonstrated strong discriminative value for objective response (overall apparent AUC = 0.90; optimism-corrected = 0.89) and was the only independent early-response indicator, outperforming anatomical response metrics (SLD: AUC = 0.57; ΔSLD: AUC = 0.63) and PD-L1 expression (AUC = 0.45). The discriminative accuracy of the SUV_max was higher in the BAI cohort (apparent AUC = 0.99; corrected = 0.97) than in the intravenous cohort (apparent AUC = 0.83; corrected = 0.83). The corroborative performance of the tumor-to-blood ratio was not significantly different from that of SUV_max.</p> Conclusions <p>⁶⁸Ga-grazytracer PET/CT is a promising early imaging biomarker for the response to chemoimmunotherapy in advanced NSCLC patients, particularly those receiving BAI-based regimens. Larger validation studies with uniform protocols are needed to validate these findings and assess its clinical utility.</p> Trial registration <p>ChiCTR2500105792, the registration date is 2025-07-10, <a href="https://www.chictr.org.cn/showproj.html?proj=275165">https://www.chictr.org.cn/showproj.html?proj=275165</a>.</p>