Combination of Cryo‐Shocked M1 Macrophages and Lonidamine Nanodrugs Enables Potent Chemo‐Immunotherapy

Abstract Therapeutics targeting immune checkpoints have achieved astonishing clinical success in cancer treatment. However, these therapies can hardly adapt to immunologically “cold” tumors featuring insufficient and exhausted tumor‐infiltrating lymphocytes as well as low immunogenicity. Herein, a two‐pronged strategy is presented by combining cryo‐shocked M1 macrophages (CSMs) and CD47‐targeted lonidamine nanodrugs (CLNDN) for reprograming the immunosuppressive tumor microenvironment (TME). CSMs induce durable polarization of tumor‐associated macrophages (TAMs) into the immunostimulatory M1 phenotype through the TLR2/MAPK signaling and also elevate CD47 expression in tumor cells, which in turn facilitates the targeted delivery of CLNDN into tumor cells. CLNDN trigger tumor cell‐specific pyroptosis through the caspase‐3/GSDME pathway and lead to the release of damage‐associated molecular patterns. Consequently, the combination of CSM and CLNDN synergistically boosts immune infiltration and tumor cell immunogenicity within the TME, effectively reverting tumor immunosuppression. This combination achieves potent antitumor effects and induces long‐term immune memory against tumor metastasis and recurrence. This work demonstrates for the first time TAM polarization by using cryo‐shocked macrophages and highlights its coordination with tumor pyroptosis for igniting tumor immunity, opening up a new avenue for robust cancer immunotherapy.