Resistance in the edges: a relational framework for treatment resistance in genitourinary cancers

Treatment resistance is usually attributed to genetic or adaptive changes within tumor cells. Here, we propose that, in some tumors, resistance also depends on specific interactions between malignant and non-malignant cells. We define relational resistance as a resistant phenotype that requires the functional organization of particular intercellular relationships. This concept is narrower than microenvironment-mediated resistance: the presence of stromal, immune, or vascular cells is not sufficient to establish relational resistance; a defined interaction must contribute functionally to treatment failure. We organize evidence along a five-step sequence: predicted edge, spatial support, functional edge, relational dependency, and therapeutic vulnerability. Genitourinary cancers illustrate different positions along this sequence: bladder cancer provides a predicted CD6-ALCAM edge with independent clinical association but without targeted perturbation; prostate cancer provides myeloid circuits with preclinical causal support and phase 1 proof-of-concept targetability; and renal cell carcinoma provides spatially organized multicellular programs with functional and preclinical perturbation support. We further propose relational memory as the hypothesis that a treatment-induced or treatment-selected interaction persists after therapy and influences response to a subsequent treatment. The framework therefore shifts the therapeutic question from which resistant cells are present to which relationships are required for resistance to persist.