Background: The current study aimed to investigate the safety and efficacy of chemotherapy with PD-1 inhibitor, tislelizumab, for stage II-IV NSCLC. Meanwhile to explore the potential biomarkers for safety and efficacy of tislelizumab plus chemotherapy in NSCLC. Methods: This was an open-label, multicenter, phase 2 trial conducted at 3 hospitals in China. Patients with treatment-naïve, stage II-IV NSCLC without EGFR/ALK driver mutations were enrolled. This study consisted of two cohorts, one cohort is potentially resectable disease (PRD) and the other is unresectable disease (URD). The PRD patients received 3-4 cycles of tislelizumab (200 mg Q3w) plus carboplatin-based chemotherapy. Candidates eligible for surgery underwent surgery, followed by adjuvant tislelizumab monotherapy for 1 year. The URD patients received platinum-based doublet chemotherapy plus tislelizumab for 4-6 cycles, followed by tislelizumab for squamous and tislelizumab in combination with pemetrexed for non-squamous, until disease progression or intolerable toxicity. Primary endpoint was safety. Secondary endpoints were efficacy, such as MPR/pCR(PRD cohort), ORR, PFS and OS, etc. Multi-omics analysis of baseline and post-treatment samples were conducted to explore the safety and efficacy for chemoimmunotherapy. (NCT05244837). Results: Between December 2020 and November 2022, a total of 100 eligible patients were enrolled and received at least one cycle of immunochemotherapy. 58 patients were with PRD, of whom 40 (68.9%) were squamous cell lung cancer. 50 (86.2%) patients were stage III disease. During neoadjuvant treatment period, 52 patients (91.2%) experienced neoadjuvant TRAEs. Most of the TRAEs were grade 1or 2. No grade 4 or 5 TRAEs was observed. The most common grade 1 or 2 TRAEs were alopecia (n = 29;50.9%), anemia (n = 25;43.9%), rash (n = 29; 50.9%). Four patients (7.0%) experienced severe TRAE of grade 3 increased ALT/AST.39 patients received surgical resection, R0 resection was performed for 38 (97.4%) patients. 29 (74.4%) achieved MPR (major pathological response), including 19 (48.7%) with a complete pathological response (pCR). 42 patients with URD were enrolled, 26 (61.9%) patients were stage IV disease. 37 patients (88.1%) experienced TRAEs. The most common grade 1 or 2 TRAEs TRAEs were anemia (n = 27; 64.3%), rash (n = 12; 57.0%). Severe TRAEs occurred in 8 (2.0%) cases, including increased ALT/AST, decreased white blood cell count etc. 29 genes were identified as differentially expressed in pre-treatment tumors from patients with pCR compared to non-pCR. Conclusions: Neoadjuvant tislelizumab plus chemotherapy was safe and effective with high MPR and manageable TRAEs in patients with PRD. For patients with URD, tislelizumab plus chemotherapy was generally well tolerated. We have identified a differential immune landscape between pCR and non-pCR tumors. Clinical trial information: NCT05244837.