CLEVER-1+ tumor-associated macrophages in gastric cancer immunotherapy resistance: integrating metabolic reprogramming and immunosuppression

Gastric cancer remains one of the leading causes of cancer-related death worldwide, with particularly high incidence in East Asia. Despite improvements in surgical resection and perioperative chemotherapy, patients with advanced or metastatic disease face a poor prognosis. The arrival of ICIs, especially anti-PD-1 antibodies such as nivolumab, has offered new treatment options. The landmark CheckMate 649 trial showed that adding nivolumab to chemotherapy significantly improves overall survival in advanced GC, gastroesophageal junction cancer, and esophageal adenocarcinoma. However, longer-term follow-up analyses have made it clear that a substantial proportion of patients either do not respond initially or relapse after an initial response. Thus, there is an urgent need to understand the mechanisms behind immunotherapy resistance.