Photothermal therapy (PTT) is a promising cancer treatment, but it has so far proven successful only with relatively small subcutaneous tumors in animal models. Treating larger tumors (≈200 mm 3 ) is challenging because most PTT materials do not efficiently reach the hypoxic, avascular center of tumors, and the immunosuppressive tumor microenvironment prevents T cells from fighting against residual tumor cells, thereby allowing recurrence and metastasis. Here, the widely used PTT material polydopamine is coated on the surface of the facultative anaerobe Salmonella VNP20009, which can penetrate deep into larger tumors. The coated bacteria are intravenously injected followed by near-infrared laser irradiation at the tumor site, combined with a local inoculation of phospholipid-based phase separation gel containing the anti-programmed cell death-1 peptide AUNP-12. The gel releases AUNP-12 sustainably during 42 days, maintaining the tumor microenvironment as immunopermissive. Using a mouse model of melanoma, this triple combination of biotherapy, PTT, and sustainable programmed cell death-1 (PD-1) blockade shows high efficiency on eliciting robust antitumor immune responses and eliminating relatively large tumors in 50% of animals within 80 days. Thus, the results shed new light on a previously unrecognized immunological facet of bacteria-mediated therapy, and this innovative triple therapy may be a powerful cancer immunotherapy tool.

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Whole‐cell vaccines that provide broad‐spectrum antigens have been explored for recent decades. But so far, they have revealed limited success in clinical trials, possibly owing to their inefficiency in targeting immune organs and antigen‐presenting cells (APCs). Herein, a facile strategy is developed to convert the whole‐cell vaccines into the nanoscale size to promote their lymphatic migration and subsequent intracellular antigen presentation to maximize immune responses. Briefly, the study designs a multiple antigen delivery platform based on alum‐induced and cancer/bacterial cell membrane coated protein antigen nanoparticles. Through a simple two‐step vortex‐sonification method, a universal carrier‐free nano‐vaccine without additional excipients could be quickly fabricated. After subcutaneous vaccination, the developed nanovaccines rapidly migrate to lymph nodes, leading to their effective uptake by lymph node‐resident APCs, and subsequent antigen presentation and activation of downstream immune processes. Overall, the described promising work offers a safe, effective, facile, and widely applicable vaccine strategy, which has great potential for clinical transformation.