Emerging role of microRNAs as modulators of the tumor immune microenvironment

The advent of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape of several malignancies, but durable clinical benefits are only observed in a subset of patients. Primary and acquired resistance to immunotherapy, largely driven by an immunosuppressive tumor immune microenvironment (TIME), remains among the most critical hurdles to overcome. Amid the molecular regulators orchestrating immune evasion, tumor-derived microRNAs (miRNAs) have emerged as pivotal players. These small non-coding RNAs reshape the TIME through diverse mechanisms, including impairment of antigen presentation, modulation of immune checkpoint pathways, suppression of cytotoxic T and NK cell activity, induction of regulatory immune populations, and reprogramming of stromal and metabolic networks. This review explores the multifaceted contribution of miRNAs to ICI resistance and discusses innovative therapeutic strategies aimed at targeting dysregulated miRNAs, either through inhibition of oncomiRs or restoration of tumor-suppressors, with the goal of reprogramming the TIME toward an immunocompetent state. The clinical implementation of combination regimens of miRNA therapeutics with ICIs remains limited, highlighting the need to test these combinations in advanced preclinical models that faithfully recapitulate the human TIME. Such models could provide an optimal platform to integrate miRNA therapeutics into immuno-oncology strategies, ultimately expanding the benefits of ICIs to a broader patient population.