A novel radio-immunotherapy strategy: Gut microbiota metabolite combined with radioactive hydrogel for the treatment of low rectal cancer

Abstract

Colorectal cancer (CRC), especially low rectal cancer, often requires surgical resection of the anus, which severely affects the quality of life of patients. This study aims to develop a novel treatment method that can effectively control tumor growth while preserving anal function. We design a radioactive hydrogel (¹⁷⁷Lu-RH) based on the cross-linking of metal ions and sodium alginate, which can be directly injected into the tumor to achieve local radiotherapy. In mouse experiments, we observe significant differences in the therapeutic efficacy of ¹⁷⁷Lu-RH among treated mice. Through 16S rDNA microbial diversity and targeted metabolomics studies, it has been revealed that the intestinal microbiota, particularly the Rikenella bacteria, and their metabolite propionate, are positively correlated with a favorable treatment response. We subsequently select the genus Rikenella, which exhibit a significantly higher abundance in the near-complete response (nCR) compared to the partial response (PR) group, for further mechanistic investigation. We discover that propionate, a metabolite produced by Rikenella, plays a crucial role in promoting tumor cell apoptosis and may augment the efficacy of tumor immunotherapy. Therefore, we improve the radioactive hydrogel by adding sodium propionate (SP) to form ¹⁷⁷Lu-RH@SP. In vivo experiments show that ¹⁷⁷Lu-RH@SP combined with anti-programmed death ligand 1 (αPD-L1) not only inhibits tumor growth but also promotes DC maturation and reverses T cell exhaustion, thereby enhancing the efficacy of tumor immunotherapy. Our work provides a new approach for the treatment of low rectal tumors, with the potential to improve the prognosis and quality of life for patients.