M2‐Like TAMs Function Reversal Contributes to Breast Cancer Eradication by Combination Dual Immune Checkpoint Blockade and Photothermal Therapy

Abstract Immune checkpoint inhibitor (ICI) therapy is considered to be a revolutionary anti‐tumor strategy that may surpass other traditional therapies. Breast cancer is particularly suitable for it theoretically due to upregulation of programmed cell death 1 (PD‐1) / programmed cell death ligand 1 (PD‐L1) immune checkpoint pathway which exhausts the adaptive immune response mediated by T lymphocytes. However, its blockades exhibit very little effect in breast cancer, owing to the lack of T lymphocytes pre‐infiltration and co‐existing of intricate immune negative microenvironment including the macrophage‐suppressed “Don't eat me” CD47 signal overexpression. Herein, a stimuli‐responsive multifunctional nanoplatform (ZIF‐PQ‐PDA‐AUN) is built. Its photothermal therapy can promote the infiltration of T lymphocytes in addition to ablating tumor cells and AUNP‐12 and PQ912 further boost both the innate and adaptive immune reactions by cutting off PD‐L1 and CD47 signals, respectively. In contrast to earlier single immunotherapy, the nanocomposites exhibit a stronger anti‐tumor immune effect without obvious autoimmune side effects, promoting infiltration of T lymphocyte into the tumor site and strengthening phagocytosis of macrophages, even more exciting, significantly reversing pro‐tumor M2‐like tumor‐associated macrophages (TAMs) to anti‐tumor M1‐like TAMs. The research may provide a promising strategy to develop high‐efficient and low‐toxic immunotherapy based on nanotechnology.