双重抑制 TGFβ信号通路和 CSF1/CSF1R 可重编程肿瘤浸润巨噬细胞，并通过抑制 PD-L1 改善化疗反应

TGFβ contributes to chemoresistance in advanced colorectal cancer (CRC) via diverse immune-microenvironment mechanisms.

Here, we found that cancer cell autonomous TGFβ directly triggered tumor programmed cell death 1 ligand 1 (PD-L1) upregulation, resulting in resistance to chemotherapy. Inhibition of tumor PD-L1 expression sensitized cancer cells to chemotherapy, reduced lung metastasis and increased the influx of CD8 + T cells.

However, chemorefractory cancer cell-derived CSF1 recruited TAMs for TGFβ-mediated PD-L1 upregulation via a vicious cycle. High infiltration of macrophages was clinically correlated with the status of tumor PD-L1 after chemotherapy treatment in CRC patients.

We found that depletion of immunosuppressive CSF1R + TAM infiltration and blockade of the TGFβ receptor resulted in an increased influx of cytotoxic CD8 + T and effector memory CD8 + cells, a reduction in regulatory T cells, and a synergistic inhibition of tumor growth when combined with chemotherapy.

These findings show that CSF1R + TAMs and TGFβ are the dominant components that regulate PD-L1 expression within the immunosuppressive tumor microenvironment, providing a therapeutic strategy for advanced CRC patients.