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.