Therapy-induced androgen receptor signaling as a candidate upstream driver of B7-H3–linked immune exclusion in melanoma: mechanisms and translational opportunities

Melanoma frequently develops resistance to BRAF/MEK–targeted therapy and immune checkpoint blockade (ICB), often through therapy-driven tumor state transitions that include immune exclusion, transcriptional plasticity, and microenvironmental remodeling. B7-H3 (CD276) has been linked to immune-cold states and is being pursued as a therapeutic target. Yet, the upstream regulators that promote or stabilize B7-H3 immune exclusion in melanoma remain incompletely defined. Here, we propose a testable framework in which therapeutic pressure increases tumor-intrinsic androgen receptor (AR) signaling, which may promote or reinforce a B7-H3–linked immune-excluded resistance program. As a hypothesis-generating human anchor, in melanoma patients treated with anti-CTLA-4, AR and B7-H3 show no pre-treatment association, but a positive association emerges post-treatment. To avoid over-reliance on melanoma-specific preliminary observations, we integrate mechanistic precedent from other tumor contexts in which B7-H3 expression is shaped by defined signaling and epigenetic programs, including reported AR binding proximal to B7-H3 in prostate cancer and upstream control by stress- and growth-factor pathways. We then outline falsifiable mechanisms by which AR could interact with these regulatory nodes to increase B7-H3 output and barrier-like immune exclusion, and we highlight translational opportunities to therapeutically disrupt the AR–B7-H3 axis through modulation of the AR pathway and/or B7-H3–directed agents. This Perspective defines near-term experiments and study designs to validate directionality, delineate the relevant resistant tumor states, and establish a rational basis for combination therapy.