The Challenges Faced by Immune Checkpoint Inhibitors and Strategies to Enhance Their Efficacy

Cancer has remained to be a huge global threat in 21 centuries. The immune checkpoint inhibitors (ICIs) mark a huge breakthrough in cancer immunotherapy by reactivating T-cell-mediated anti-tumor responses through blockade of inhibitory pathways like CTLA-4 and PD1/PDL1. Despite their clinical success, ICIs face some limitations. One of them is varying response rate. Some patients never respond to ICIs (primary resistance) and some others show resistance after initial response to ICIs (acquired resistance). Moreover, the incidence of immune-related adverse events (irAEs) that result from aberrant immune system activation increases with the use of ICIs which further complicates treatment and limits the use of ICIs. To overcome these limitations, biomarkers that predict the efficacy of ICIs like PDL1 expression, microsatellite instability (MSI-H), and mismatch repair deficiency (DMMR) have emerged, though sometimes not accurate. Furthermore, combination therapy that integrates different ICI agents and pair ICI with traditional cancer therapy is becoming increasingly used to overcome the resistance in mono ICI therapy. Emerging studies highlight the pivotal role of gut microbiome in modulating the response of ICIs. The gut microbiome intervention like fecal microbiota transplantation (FMT) has been proposed to increase the efficacy of ICIs. Optimizing the broader application of ICIs requires elucidating ICIs resistance mechanism to minimize the occurrence of resistance, enhancing biomarkers accuracy, and mitigating irAEs.