Multifunctional tumor vaccines carrying thalidomide regulate T cell exhaustion and ferroptosis for immunotherapy strategies

Abstract Significant advancements have been made in the development of therapeutic tumor vaccines for hepatocellular carcinoma (HCC) in the past decade. However, the application of this technique is restricted by the paucity of suitable vaccine adjuvant and vaccine formula that could enhance the anti‐cancer efficiency. Here, we demonstrate that a multifunctional tumor vaccine (MTV) that is coated with tumor membrane antigens and loaded with thalidomide (THA) to promote tumor antigen presenting and T cell activation, leading to the activation of T cells at the cancer site. The in vitro and in vivo experiments revealed that MTV significantly inhibits the progression of three types of liver cancer models: malignant ascites, subcutaneous tumors, and in situ liver cancer. As a result, MTV can enhance T cell immune memory, alleviate T cell exhaustion and reprogram cytokine delivery to induce ferroptosis in tumor cells, thus improving the effectiveness of anti‐PD‐1 immunotherapy. This synergistic approach ensures robust immunotherapeutic effects against multiple types of HCC models. Furthermore, our research highlights THA as a potent vaccine adjuvant that can directly enhance the preventive and therapeutic effects of vaccines, proposing a promising strategy for cancer prevention and immunotherapy.