How microenvironmental inflammation impacts melanoma progression remains controversial. Inflammation appears beneficial during interferon stimulated expression of checkpoint targets. However, when tipped too far, therapy-driven inflammation has been linked to debilitating autoimmune disease in cancer patients. One unanswered question is whether this inflammation also promotes melanoma dissemination. Here, drug-stressed melanomas are shown to promote progression via a pro-inflammatory secretome that activates the tumor microenvironment. Analyses showed the drug specific activation of immune recruiting cytokines and the transforming growth factor beta (TGFβ) superfamily. In coculture, TGFβ from drug-stressed melanomas resulted in the paracrine hyperactivation of cancer associated fibroblasts (CAFs) as noted by the inflammatory marker alpha smooth muscle actin (αSMA). Pharmacologic inhibition of TGFβ using SB431542 or clinically relevant EW-7197, blunted the αSMA phenotype as well as downstream phospho-SMAD activation. Invasion of melanoma spheroids in CAF cocultures resulted in enhanced invasion which could suppressed by targeted MEK inhibition (AZD6244) and TGFβ receptor blockade. Engrafted melanomas in vivo presented with the rapid expansion of peri-tumoral αSMA+ CAFs surrounding invasive micrometastatic nodules in mouse livers. We have previously reported that extracellular matrix (ECM) protein tenascin-C (TNC) is enriched at the invasive fronts of melanoma, which was recapitulated in vivo and correlated to human melanomas. Human tissue microarrays were assayed for pro-inflammatory TNC, healthy ECM marker Decorin (DCN), αSMA CAFs, and fibrotic Collagen (COL1A1) expression. We detected statistically significant increases in TNC, αSMA and COL1A1 correlating to progression and a concomitant decrease in DCN. Evidence from drug treated spheroid cocultures did not show complete suppression single cell invasion. Prompted by this, ex vivo organotypic skin organ cultures containing TNC and DCN were developed to show that the ECM provides physiological pro-and-anti invasive signals. Expression of DCN therapeutically inhibited collective and single cell invasion in this model. We also observed transcriptomic suppression of TNC and key inflamed matrisome proteins in anti-TGFβ treated CAFs, even when challenged with TGFβ conditioned media. Informed by this, we used a TNC+ vemurafenib resistant patient-derived metastatic melanoma in our xenograft model. Cohorts treated with MEK inhibitor and combination therapy with EW-7197 showed drug efficacy and tolerance with detectable decreases in αSMA and tumor burden of the spleen. Treated animals also showed reduced liver metastases compared to control. Taken together, combination therapy that blocks off-target inflammation and cancer proliferation represent an underappreciated but potentially successful strategy to halt melanoma progression. Citation Format: Andrew Bradshaw, Erica Kuo, Jelena Grahovac, Cindy Sander, Howard Edington, John M. Kirkwood, Alan Wells. The therapeutically inflamed tumor microenvironment drives melanoma progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT002.