Metronomic chemotherapy as a potential partner of immune checkpoint inhibitors for metastatic colorectal cancer treatment

The use of immune checkpoint inhibitors (ICIs) in clinical practice for the treatment of metastatic colorectal cancer (mCRC) is currently limited to patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), which comprise less than 5% of all mCRC cases. Combining ICIs with anti-angiogenic inhibitors, which modulate the tumor microenvironment, may reinforce and synergize the anti-tumor immune responses of ICIs. In mCRCs, combinations of pembrolizumab and lenvatinib have shown good efficacy in early phase trials. These results suggest the potential utility of immune modulators as partners in combination treatment with ICIs in immunologically cold microsatellite stable, as well as hot dMMR/MSI-H tumors. Unlike conventional pulsatile maximum tolerated dose chemotherapy, low-dose metronomic (LDM) chemotherapy recruits immune cells and normalizes vascular-immune crosstalk, similar to anti-angiogenic drugs. LDM chemotherapy mostly modulates the tumor stroma rather than directly killing tumor cells. Here, we review the mechanism of LDM chemotherapy in terms of immune modulation and its potential as a combination partner with ICIs for the treatment of patients with mCRC tumors, most of which are immunologically cold.