STING Agonist-Loaded Nanoparticles Promotes Positive Regulation of Type I Interferon-Dependent Radioimmunotherapy in Rectal Cancer

Hypoxia-associated radioresistance in rectal cancer (RC) has severely hampered the response to radioimmunotherapy (iRT), necessitating innovative strategies to enhance RC radiosensitivity and improve iRT efficacy. Here, a catalytic radiosensitizer, DMPtNPS, and a STING agonist, cGAMP, are integrated to overcome RC radioresistance and enhance iRT. DMPtNPS promotes efficient X-ray energy transfer to generate reactive oxygen species, while alleviating hypoxia within tumors, thereby increasing radiosensitivity. Mechanistically, the transcriptomic and immunoassay analysis reveal that the combination of DMPtNPS and RT provokes bidirectional regulatory effects on the immune response, which may potentially reduce the antitumor efficacy. To mitigate this, cGAMP is loaded into DMPtNPS to reverse the negative impact of DMPtNPS and RT on the tumor immune microenvironment (TiME) through the type I interferon-dependent pathway, which promotes cancer immunotherapy. In a bilateral tumor model, the combination treatment of RT, DMPtNPS@cGAMP, and alpha PD-1 demonstrates a durable complete response at the primary site and enhanced abscopal effect at the distant site. This study highlights the critical role of incorporating catalytic radiosensitizers and STING agonists into the iRT approach for RC. DMPtNPS and radiotherapy (RT) have a potential to decrease tumor hypoxia and enhance radiosensitivity while provoking bidirectional regulatory effects on the immune response. Loading cGAMP on DMPtNPS reverse the negative impact on the immune response and improves immunotherapy through type 1 interferon pathway. When combined with DMPtNPS@cGAMP, RT and alpha PD-1 therapy, the result is long-lasting complete response and improved abscopal effects.image