Immune checkpoint inhibitors (ICIs) have emerged as a beacon of hope for most patients with stage III non-small cell lung cancer (NSCLC) who are no longer surgical candidates. However, the literature on the use of immunotherapy in patients with NSCLC with rearranged during transfection (RET) gene fusions is scant. The present study reports the case of a 61-year-old female patient, diagnosed with stage IIIC lung adenocarcinoma, exhibiting two RET gene fusions and high programmed death-ligand 1 expression. Following four treatment cycles of tislelizumab in combination with pemetrexed and cisplatin, the patient was successfully downstaged, enabling radical surgery. The post-operative pathology analysis indicated a major pathologic response. This case study contributes to the growing body of evidence supporting the use of ICIs in treating locally advanced NSCLC with RET gene fusions.