A m⁶Avalue predictive of prostate cancer stemness, tumor immune landscape and immunotherapy response

The molecular mechanisms underpinning prostate cancer (PCa) progression are incompletely understood, and precise stratification of aggressive primary PCa (pri-PCa) from indolent ones poses a major clinical challenge. Here, we comprehensively dissect, genomically and transcriptomically, the m⁶A (N ⁶-methyladenosine) pathway as a whole in PCa. Expression, but not the genomic alteration, repertoire of the full set of 24 m⁶A regulators at the population level successfully stratifies pri-PCa into three m⁶A clusters with distinct molecular and clinical features. These three m⁶A modification patterns closely correlate with androgen receptor signaling, stemness, proliferation and tumor immunogenicity of cancer cells, and stroma activity and immune landscape of tumor microenvironment (TME). We observe a discrepancy between a potentially higher neoantigen production and a deficiency in antigen presentation processes in aggressive PCa, offering insights into the failure of immunotherapy. Identification of PCa-specific m⁶A phenotype-associated genes provides a basis for construction of m⁶Avalue to measure m⁶A methylation patterns in individual patients. Tumors with lower m⁶Avalue are relatively indolent with abundant immune cell infiltration and stroma activity. Interestingly, m⁶Avalue separates PCa TME into fibrotic and nonfibrotic phenotypes (instead of previously reported immune-proficient or -desert phenotypes in other cancer types). Significantly, m⁶Avalue can be used to predict drug response and clinical immunotherapy efficacy in both castration-resistant PCa and other cancer types. Therefore, our study establishes m⁶A methylation modification pattern as a determinant in PCa progression via impacting cancer cell aggressiveness and TME remodeling.