A bioorthogonal probiotic platform spatiotemporally releases nanobodies in deep tumor for cancer chemoimmunotherapy

The effectiveness of immune checkpoint blockade therapies in treating solid tumors is hindered by the limited activation of the tumor immune microenvironment within deep tumors. Immunogenic cell death offers a promising method to enhance anti-tumor immune responses. Integrating these two approaches in cancer chemoimmunotherapy presents a novel perspective. Here, a self-mineralized bioorthogonal probiotic platform with the expression of anti-PD-L1 nanobodies was developed for cancer chemoimmunotherapy. This platform selectively accumulated and deeply penetrated into tumor tissues, where the palladium-mineralized probiotics catalyzed bioorthogonal bond-cleavage to generate chemotherapeutic drugs and induced immunogenic cell death. Under laser irradiation, the indocyanine green modified probiotics were ruptured and released nanobodies which effectively suppressed tumor immune evasion and ultimately led to the tumor-specific immune responses. This innovative platform resulted in significant inhibition of tumor growth and lung metastasis. Overall, these findings suggest that synergistically enhancing antitumor immunity through the induction of immunogenic cell death via bioorthogonality and PD-L1 blocking as a therapeutic strategy could improve cancer chemoimmunotherapy.