Decoding functional impact of epigenetic regulator mutations on ligand–receptor interaction perturbations for evaluation of cancer immunotherapy

Cellular crosstalk mediated by ligand–receptor interactions largely complicates the tumour ecosystem, resulting in heterogeneous tumour microenvironments that affect immune response and clinical benefits from immunotherapy. Epigenetic mechanisms are pivotal to expression changes of immune‐related genes and can modulate the anti‐tumour immune response. However, the functional consequences of disrupted epigenetic regulators (ERs) on ligand–receptor interactions in the tumour microenvironment remain largely unexplored. Here, we proposed mutations of ERs in perturbed interactions (MERIN), a molecular network‐based approach that incorporates multi‐omics data, to infer the potential consequences of ER mutations on ligand–receptor interaction perturbations. Leveraging cancer genomic profiles and molecular interaction data, we comprehensively decoded the functional consequences of ER mutations on dysregulated ligand–receptor interactions across 33 cancers. The dysregulated ligand–receptor genes were indeed enriched in cancer and immune‐related function. We demonstrated the potential significance of PD1–PDL1 interaction‐related ER mutations in stratifying cancer patients from multiple independent data cohorts. The ER mutation group showed distinct immunological characterizations and prognoses. Furthermore, we highlighted that the ER mutations could potentially predict clinical outcomes of immunotherapy. Our computational and clinical assessment underscore the utility of MERIN for elucidating the functional relevance of ER mutations in cancer immune response, potentially aiding patients' stratification for immunotherapy.