Modulation of tumor environment in colorectal cancer - could gut microbiota be a key player?

The treatment paradigm of neoplastic diseases has dramatically shifted with the introduction of immune checkpoint inhibitors (ICI). They induce a durable response in a wide variety of solid tumors, but this response depends on the infiltration of lymphocytes capable of recognizing and killing tumor cells. The primary predictor of intrinsic immune resistance to ICIs is the absence of lymphocytes in the tumor, the so-called "cold tumors". Colorectal cancer (CRC) remains one of the most common and challenging cancer, but it is not traditionally considered a highly immunogenic tumor. In fact, immunotherapy showed a remarkable antitumoral activity only on a small subset of CRC patients - the ones with microsatellite instability-high/deficient DNA mismatch repair (MSI-H/dMMR). Most CRCs display a molecular microsatellite stability/proficient DNA mismatch repair (MSS/pMMR) profile, so strategies to improve tumor immunogenicity are crucial. Therefore, ongoing studies investigate new approaches to convert "cold" to "hot" tumors in MSS/pMMR CRCs. In addition, it has been described that gut microbiota influences tumor development and the host immune response. Hence, the microbiota may modulate the immune response, becoming a promising biomarker to identify patients who will benefit from ICIs. Future data will help to better understand microbiota mechanisms and their role in ICI efficacy. Precision medicine in cancer treatment could involve modulation of the microbiota through different strategies to improve tumor immunogenicity. In this review, we aim to present the potential relationship between gut microbiota and the modulation of the immune system and the hypothetical implications in CRC treatment, namely ICIs.