Core Viewpoint - The article discusses a novel strategy to improve CAR-T cell therapy for osteosarcoma by utilizing cuproptosis, which enhances the efficacy of the treatment in a challenging tumor microenvironment [3][4][11]. Group 1: Osteosarcoma and Current Treatment Challenges - Osteosarcoma is a common malignant tumor with a low survival rate of approximately 15%-17% for patients receiving only surgical treatment, and a stagnated 5-year survival rate of about 60% for those undergoing combined surgery and chemotherapy over the past 30 years [1]. - Traditional chemotherapy often leads to drug resistance and tumor recurrence, highlighting the urgent need for improved treatment strategies [1]. Group 2: Novel Research Findings - A study published by a team from Southern Medical University proposes a new approach using cuproptosis to enhance CAR-T cell therapy in osteosarcoma [2]. - The research indicates that copper death can lower PD-L1 expression in osteosarcoma cells, which is positively correlated with copper death-related gene expression [8][11]. - The study developed a biocompatible nanodrug composed of tetrahedral framework nucleic acids (tFNA), elesclomol-Cu, and anti-PD-L1 antibodies to induce copper death and block the PD-1-PD-L1 signaling axis, thereby reshaping the immunosuppressive tumor microenvironment [3][9]. Group 3: Implications for CAR-T Cell Therapy - The results demonstrate that the use of this nanodrug significantly enhances CAR-T cell infiltration and anti-tumor activity in both in situ and recurrent osteosarcoma models [10]. - This research provides insights into the relationship between copper metabolism and PD-L1 expression, offering a potential universal method to improve adoptive cell therapy for solid tumors [4].