Enhancing targeted strategies for cancer immunotherapy by elucidating mRNA processing mechanisms

Immune checkpoint inhibitors have transformed the landscape of cancer therapy; however, the challenge that most patients do not achieve durable benefits urgently necessitates the development of new strategies that extend beyond mere T-cell activation. mRNA processing—comprising alternative splicing, RNA modifications, and RNA editing—establishes a dynamically regulated connection between the intrinsic characteristics of tumors and anti-tumor immunity.

This review systematically summarizes how mechanistic insights into these processes can be translated into concrete approaches that enhance the precision of immunotherapy. We first outline how the widely dysregulated splicing events in tumor cells produce abundant neoantigens at a frequency that significantly exceeds that of gene mutations.

A subset of these splice isoforms is shared among patients, offering a unique antigen resource for the development of ‘off-the-shelf’ mRNA vaccines, thereby circumventing the manufacturing bottleneck associated with personalized vaccines. Concurrently, RNA modifications driven by N6-methyladenosine (m6A) create an immunosuppressive network at the epitranscriptomics level by bidirectionally modulating the stability of immune checkpoint molecules, e.g., Programmed Death-Ligand 1 (PD-L1), and the functional polarization of macrophages and dendritic cells.