The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis via a dynamic bidirectional tumor–stroma dialog. Here, we show that homologous recombination-defective (HRD) neoplastic epithelium reprograms its TME in a genotype-specific manner to promote cancer aggressiveness. Autochthonous mouse models, co-culture systems, and human PDAC specimens revealed that tumoral ATM serine/threonine kinase status impacts cancer-associated fibroblast fate towards αSMA+ myofibroblastic (myCAF) differentiation, while P53 operates mostly tumor cell intrinsic. Vice versa, myCAFs foster cancer aggressiveness and specific chemoresistance patterns. Secretomics, proteomics, and in vitro approaches uncovered a greater TGF-β1 release in ATM-deficient cells associated with an enhanced reactive oxygen species/actomyosin-mediated mechanism. Pharmacological interference with TGF-β signaling reverts myofibroblast differentiation, chemoresistance, and tumor promotion in various ATM-deficient PDAC models. Overall, our findings demonstrate specific TME reprogramming by HRD PDACs towards a cancer-promoting fate, and their eligibility for combinatorial therapies targeting intrinsic vulnerabilities and extrinsic tumor–stroma oncogenic crosstalks.