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Background Activin A, a homodimer of Inhibin βα (INHBA), belongs to the TGF-β superfamily and recent research has expanded our understanding of its role in tissue fibrosis, cachexia, and immune cell modulation. Clinically, cancer patients with high INHBA expression (eg: Pancreatic Ductal Adenocarcinoma) have exhibited a poor survival prognosis and a positive correlation to overall immune exclusion. Functionally similar to TGF-β, Activin A activates the SMAD2/3 signaling pathway leading to Cancer Associated Fibroblast (CAF) activation and subsequent immunosuppression in the tumor microenvironment. Here, we showcase fibroblast derived Activin A as an attractive target which acts primarily on tumor cells to regulate chemokine mediating immune infiltration into the tumor microenvironment.Methods To better understand the role of Activin A overall in the tumor microenvironment, we overexpressed INHBA in Activin A-low CT26 tumors followed by measuring in vivo growth kinetics and quantifying ex vivo based readouts.Results INHBA overexpressed CT26 tumor cells had an increased tumor burden, correlating with a significant reduction in T cell and DC subsets. Immunohistochemistry analysis of these tumors revealed a significant increase in tumor cells, aSMA + CAFs, and endothelial cells additionally suggesting Activin A’s role in tumor progression. Differential gene expression analysis of these tumors revealed a significant decrease in chemokines mediating cDC and T cell recruitment. The role of stromal specific Activin A was further examined via a co-injection study of tumor cells with Activin A producing or knockdown fibroblasts.Conclusions Overall, these studies provide context elucidating Activin A’s role in regulating chemokine mediated immune infiltrate through a tumor-stromal crosstalk resulting in an overall immunosuppressive tumor landscape.