{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:08:29Z","timestamp":1790352509777,"version":"4.1.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Melanoma frequently develops resistance to BRAF\/MEK\u2013targeted 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\u2013linked 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\u2013B7-H3 axis through modulation of the AR pathway and\/or B7-H3\u2013directed 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.<\/jats:p>","DOI":"10.3389\/fmed.2026.1807470","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:48:33Z","timestamp":1774421313000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Therapy-induced androgen receptor signaling as a candidate upstream driver of B7-H3\u2013linked immune exclusion in melanoma: mechanisms and translational opportunities"],"prefix":"10.3389","volume":"13","author":[{"given":"Adrian P.","family":"Mansini","sequence":"first","affiliation":[{"name":"Department of Dermatology, Rush University Medical Center","place":["Chicago, IL, United States"]},{"name":"Department of Urology, Rush University Medical Center","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Hyngstrom","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, Rush University Medical Center","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle T.","family":"Amber","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Rush University Medical Center","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/s41416-020-01144-5","article-title":"Understanding the impact of sex and stage differences on melanoma cancer patient survival: a SEER-based study","volume":"124","author":"Smith","year":"2021","journal-title":"Br J 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