Rbbp8nl contributes to resistance to anticancer immunotherapy by creating a non-inflamed tumor microenvironment and attenuating CD8+ T cell infiltration

Abstract Immune checkpoint blockade (ICB) monotherapy has limited efficacy, and it is crucial to explore predictive markers for the efficacy of immunotherapy and its use as new therapeutic targets or sensitization targets in combination with immunotherapy. Pan-cancer research using RNA sequencing data from The Cancer Genome Atlas (TCGA) revealed that RBBP8NL is particularly overexpressed in the tumor microenvironment (TME) of different malignancies. Additionally, there is a negative correlation between RBBP8NL and immune modulators, T cell inflammatory scores, immunological checkpoints, cancer immune cycle, and tumor-infiltrating immune cells (TIICs), so it can be inferred that RBBP8NL shapes the non-inflammatory TME in BLCA. BLCA patients with high RBBP8NL expression have a low response rate to immunotherapy, and they are more likely to experience hyperprogression of the illness. Interestingly, anti-RBBP8NL with immunotherapy could work better together than they do separately. According to the results of the multi-omics analysis, RBBP8NL inhibits the recruitment of cytotoxic lymphocytes. Furthermore, RBBP8NL’s predictive significance for immunotherapy success has been confirmed across several immunotherapy cohorts. In summary, RBBP8NL is a crucial component of the TME and a developing target for binding to ICB as well as a biomarker to direct precision medicine.