N6-methyladenosine (m6A) is often characterized as a double-edged sword in cancer, a description that highlights the opposing effects of m6A without elucidating the underlying mechanisms. This review explores whether the perceived contradiction can be clarified by analyzing m6A functions across distinct cellular compartments. Focusing on bladder, renal, and prostate cancers, which collectively represent a broad spectrum of immunogenicity and frequently utilize checkpoint blockade therapy, the study identifies m6A writers, erasers, and readers within each tumor type. The differing functions of these components in relation to surrounding immune cells, including macrophages, T cells, and dendritic cells, are examined. Within the tumor compartment, each regulatory element yields divergent outcomes based on tumor type and molecular targets. Conversely, in the immune compartment, their overall impact on antitumor immunity may be contradictory; for instance, a regulator that promotes tumor cell proliferation could simultaneously suppress or enable the immune response against the same tumor. These observations are synthesized into a compartment-resolved conceptual model. This model posits that the apparent direction of an m6A perturbation represents the cumulative, and potentially conflicting, impacts on tumor and immune cells, influenced by cell identity, target transcripts, reader composition, and local metabolic or spatial conditions. The innovation resides not in the observation of m6A's context dependence but in the explicit consideration of tumor-cell and immune-cell effects as distinct components requiring simultaneous examination in urological tumors. This synthesis aims to organize disparate findings, propose experimentally testable explanations for conflicting outcomes, and emphasize the necessity of cell-type-resolved measurements. However, it does not constitute a validated predictive algorithm, as the relative significance of compartments and contextual variables remains unquantified and untested.

N6-methyladenosine (m6A), urologic cancer, tumor microenvironment, tumor-associated macrophage, immune checkpoint blockade, RNA methylation readers