In situ reprogramming of tumor-associated macrophages enhances cancer immunotherapy

In situ reprogramming of tumor associated macrophages (TAMs) to resurge their phagocytic ability holds great potential in cancer treatment. However, most of currently existing TAMs-reshaping approaches fail to effectively reprogram TAMs due to low efficiency, poor specificity, and potential immune side effects. Herein, we report a strategy called molecularly imprinted lysosomal nanodegrader (MILND) for resurging the phagocytosis of macrophages and reversing the "don't eat me" CD47-SIRP alpha signal via degrading SIRP alpha in lysosomes. The MILND, which was rationally engineered by controllable molecular imprinting using the N-terminal epitope of SIRP alpha as template, could specifically bind SIPR alpha on TAMs. Upon being engulfed by TAMs via endocytosis, the MILNDSIRP alpha complex was transferred to lysosomes for degradation. The degradation of SIRP alpha induced a cascade reaction of the downstream PI3K signaling pathway to resurging the phagocytic and recognition capability of TAMs towards cancer cells. Ultimately, MILND resulted in a subsequent series of anti-tumor effects. Benefiting from this, MILND effectively sensitized the immune microenvironment and amplified CD8+ T cell responses, leading to substantial tumor growth inhibition in tumor-bearing mouse model. Thus, this work provides an efficient and versatile immunomodulatory strategy for enhanced antitumor immunotherapy.