Background: Perioperative therapy, especially whether preoperative neoadjuvant therapy (NAT) can improve R0 resection rate and prolong overall survival of patients with locally advanced gastric cancer, has been paid more and more attention. NAT is mainly defined as a preoperative chemotherapy or chemoradiotherapy, aiming at increasing radical resection rate by downstaging tumor and eliminating micrometastases. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1-4 and PDGFRα/β, which effectively blocks tumor neovascularization and growth. Previous phase I/II clinical trials suggested that penpulimab monotherapy as second-line therapy was well tolerated and showed clinical anti-tumor activity in gastric or gastroesophageal junction carcinoma (GC/GEJ) (NCT03352531, NCT04172506). It was demonstrated an objective response rate (ORR) of 26.3%, a disease control rate (DCR) of 42.1% in GC/GEJ patients (pts) using penpulimab monotherapy. This trial was designed to assess the feasibility and efficacy of penpulimab plus anlotinib combined with chemotherapy in perioperative treatment of pts with locally advanced gastric cancer. Methods: This is a multi-center, prospective, single-arm, phase II study. Resectable GC pts with TNM stage T3~4N+M0 per AJCC^8th, ECOG PS 0-1, were enrolled and treated with 3 cycles of preoperative penpulimab (200mg, iv, d1, q3w) + anlotinib (12mg, qd, d1-d14, q3w)+ SOX (oxaliplatin 130mg/m², iv, d1 and S-1 40-60mg, po, bid, d1-14, q3w), and 12 months of postoperative adjuvant therapy formulated by investigators according to the individual situation of the pts. Primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included major pathologic response (MPR) rate, disease free survival (DFS), objective response rate (ORR), R0 resection rate and safety. Based on a two-sided test for one proportion with 5.0% type I error, 80% power to detect an improvement in the rate of pCR from 13% to 29%, there will be 57 pts enrolled considering 10% of pts dropping out. Clinical trial information: NCT05385900.