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Herein, we profiled the landscape of the BRAF regulatome identifying a novel transcription factor, TFAP2A, newly linking BRAF\/MEK drug resistance to antitumor immunity. Specifically, we found that BRAF\/MEK inhibitors significantly upregulate TFAP2A. Further, genetic disruption of TFAP2A overcomes BRAF\/MEK-inhibitor resistance, promotes stromal enrichment, and enhances intratumoral infiltration of macrophages in an immune-compromised mouse model. In a syngeneic mouse model, TFAP2a knockout not only suppresses tumor growth but also induces potent anti-tumor tertiary lymphoid structures (TLSs). Single cell transcriptomics revealed that the absence of TFAP2A shapes the antitumor microenvironment with an influx of M1-like macrophages, CD8+ T cells and mature dendritic cells. By identifying TFAP2A as a shared driver of both targeted therapy resistance and immunosuppression, our work offers a one-stone-two-bird strategy to overcome drug resistance and elicit antitumor immunity.<\/jats:p>","DOI":"10.64898\/2026.07.08.735861","type":"posted-content","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T09:30:25Z","timestamp":1783675825000},"source":"Crossref","is-referenced-by-count":0,"title":["TFAP2A links drug resistance to antitumor immunity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1710-1882","authenticated-orcid":false,"given":"Haiwei","family":"Mou","sequence":"first","affiliation":[{"name":"Melanoma Research Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Yakovishina","sequence":"additional","affiliation":[{"name":"Melanoma Research Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 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