Probiotic-mediated tumor microenvironment reprogramming with protease-sensitive interleukin-15 and photothermal therapy

T cell inadequacy or exhaustion often causes the failure of immune checkpoint blockade (ICB)-based immunotherapy. Interleukin-15 (IL-15) has been used to prime the tumor microenvironment (TME) to boost the efficiency of immunotherapy. However, its clinical application is hindered by systemic toxicity and low intratumoral concentrations. Here, we engineer the probiotic Escherichia coli Nissle 1917 to deliver IL-15 and croconium dye, enabling the TME-responsive release of IL-15 and amplifying the antitumor effect through photothermal therapy. This promotes the recruitment of antigen-presenting cells and T cells and the expansion of T/natural killer cells induced by IL-15. Consequently, it halts the tumor growth and induces systemic memory T cell production. This approach combined with ICBs generates prominent synergistic effects across various immune-hot and immune-cold tumors. This study provides a strategy for targeted delivery of cytokines, demonstrating its high potential for TME reprogramming when combined with immunogenic cell death inducers.