mRNA processing in cancer immunotherapy: emerging targets, resistance mechanisms, and therapeutic opportunities

Abstract

Cancer immunotherapy has improved outcomes across many tumor types, but primary and acquired resistance, tumor heterogeneity and a shortage of safe targets remain unresolved. Part of this gap arises because tumor cells evade immune recognition not only through genomic mutation but also through post-transcriptional mRNA processing, a network comprising 5′ capping, splicing, alternative polyadenylation (APA), RNA editing, epitranscriptomic modification, nonsense-mediated decay (NMD), RNA stability and translational control. These processes govern antigen presentation, transcript degradation, checkpoint expression and the suppression of innate immune sensing. Here we examine how mRNA processing can extend the target space of cancer immunotherapy. We consider alternative splicing as a source of tumor-specific isoforms, public neoantigens and chimeric antigen receptor (CAR) or T-cell receptor (TCR)-based targets; the effect of APA and 3′UTR remodeling on checkpoints such as PD-L1; the role of m6A, ac4C and other epitranscriptomic marks in antigen presentation, interferon signaling and the tumor microenvironment; the contribution of ADAR1-mediated editing to immunotherapy resistance through suppressed dsRNA and Z-RNA sensing; and the function of NMD as an antigen filter. We also review the discovery technologies that make these targets accessible, and assess the current state of clinical translation, including agent development, target specificity, patient selection, biomarkers and safety. mRNA processing-derived targets offer new sources of antigens, biomarkers and combination strategies in tumors with low mutational burden or refractory to checkpoint blockade. Realizing this will require validation of RNA-level candidates at the protein and HLA-peptide level, together with attention to tumor-normal specificity, HLA restriction, tumor heterogeneity and toxicity.