Cuproptosis as a novel predictor of immunotherapy response and shapes the immune landscape in pan-cancer analysis

The heterogeneity of cancer renders its response to immunotherapy elusive, warranting the identification of robust biomarkers for evaluation. As a form of recently defined regulated cell death (RCD), cuproptosis is driven by copper-dependent proteotoxic stress in mitochondria tricarboxylic acid cycle (TCA cycle), exerting a sophisticated role in antitumor immunity, yet remains poorly understood. Here, we established a cuproptosis score to characterize the immune landscape across 23 human cancers and established the correlation of cuproptosis score with patient immunotherapy outcomes through multi-omics analysis. Bulk and single-cell transcriptomic analysis revealed that with cuproptosis-low patients tend to have improved immunotherapy outcomes compared to those with high cuproptosis scores, with increased immune infiltration and function, as well as abundant cytokines, checkpoints and major histocompatibility complex (MHC) molecules expression. Spatial transcriptomic analysis indicated that immune cells exhibited higher cuproptosis scores than tumor cells, hinting that immune cells are vulnerable to cuproptosis. Further metabolomic and transcriptomic analysis of underlying intrinsic features revealed that cuproptosis-low tumors exhibited a metabolic and signaling pathway profile enrichment favoring antitumor immunity and potent immunogenicity. Overall, our multi-omics analysis suggests cuproptosis score as a robust biomarker for immunotherapy benefit in multiple cancers, reveals cuproptosis-related extrinsic and intrinsic immune landscapes, and provides a broad framework for understanding the relevance of cuproptosis to cancer immunology and clinical benefits of immunotherapy.