How to overcome tumor resistance to anti-PD-1/PD-L1 therapy by immunotherapy modifying the tumor microenvironment in MSS CRC

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death-1/anti-programmed cell death ligand-1 (anti-PD-1/PD-L1) therapy, have elicited impressive clinical outcomes in several malignancies. This is regarded as a pivotal breakthrough in cancer treatment. However, a vast majority of colorectal cancer (CRC) cases are microsatellite stable (MSS) and respond poorly to anti-PD-1/PD-L1 immunotherapies. Since ICIs serve as rescuers for immune cell-mediated cancer cell elimination, the limited efficacy of anti-PD-1/PD-L1 treatments may be attributed to the privileged tumor microenvironment (TME), which is characterized by unavailable immunosurveillance. Thus, it is essential to modify the pre-existing disordered immune system prior to the application of an anti-PD-1/PD-L1 therapy. In this review, to overcome unsatisfactory immunotherapy in CRC patients with MSS, we discussed various combination therapies based on TME reconstruction for improving the susceptibility to anti-PD-1/PD-L1 treatment.