In situ probiotic-to-postbiotic transformation for spatiotemporally controlled cancer photoimmunotherapy

Abstract Current cancer phototherapy is often hindered by suboptimal immunogenicity and inevitable immune escape. Herein, a programmable bio-hybridized phototherapeutic platform is developed by chemical grafting drug-loaded phototherapeutic nano-modules on natural facultative anaerobic probiotics. Exploiting the innate hypoxia-tropic motility of probiotics, the platform achieves robust active accumulation within tumor tissues. Under the first near-infrared (NIR) laser stimulus, the platform undergoes in situ probiotic-to-postbiotic transformation and phototherapeutic nano-modules separation, promoting the intratumoral infiltration and proliferation of immune cells by activating Toll-like receptors via the exposed pathogen-associated molecular patterns. Subsequently, the detached nano-modules realize deep tumor penetration and precise mitochondrion-intervened phototherapy under the second NIR irradiation. Synergized with indoleamine 2,3-dioxygenase (IDO) inhibition to block immune evasion, this cascaded strategy successfully converts the primary tumor into an autologous “tumor vaccine depot”. Compared with conventional phototherapeutic agents, the proposed probiotic platform can significantly increase the systemic proportion of key immune cells, like matured dendritic cells (~296.35%) and cytotoxic T cells (~173.33%), arousing systemic immunostimulation to potently inhibit distant and metastatic tumor nodules. Overall, the bio-hybridized probiotic platform represents a broad-spectrum paradigm for spatiotemporally controlled cancer photoimmunotherapy.