Tumor-associated fibroblasts (TAFs) have been implicated in all steps of tumor progression in solid tumors, and frequently exhibit an activated phenotype, which renders them hypercontractile. In addition, activated fibroblasts/myofibroblasts deposit large amounts of collagen and other fibrotic extracellular matrix (ECM) components, with collectively contribute to the abnormal tissue stiffening that feeds back to activate fibroblasts and stiffen the tumor even further.  Despite all the latter evidences of an altered mechanical microenvironment within the tumor microenvironment, the mechanisms underlying the abnormal mechanobiology of TAFs remains poorly understood. To address this gap of knowledge, we assembled a collection of TAFs and paired control fibroblasts from two major lung cancer subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC), which are among the major causes of cancer-related deaths worldwide.  Using our lung TAF collection, we analyzed the role of extrinsic (i.e. matrix stiffening and TGF-β) and intrinsic (i.e. intracellular signaling) factors in the aberrant mechanobiology of lung TAFs. We found that the aberrant phenotye of lung TAFs is associated with a global epigenetic reprogramming through altered DNA methylation in both ADC-TAFs and SCC-TAFs, and that such reprogramming is poorly induced by matrix stiffening, and only partially elicited by the potent fibroblast activator TGF-β. These results revealed that the aberrant DNA epigenome of lung TAFs is driven by extrinsic processes other than matrix stiffening and TGF-β. Interestingly, the top gene whose transcription was more robustly down-regulated through DNA methylation was SMAD3, which is a very important transcription factor of the TGF-β pathway and a critical regulator of fibroblast activation. Concomitantly with SMAD3 epigenetic silencing, we observed an hyperresponse of TAFs to TGF-β compared to control fibroblasts in terms of ECM deposition and contractility, thereby supporting that aberrant SMAD3 signaling may underlie the expansion of a stiff and activated tumor microenvironment. On the other hand, we analyzed the role of matrix stiffening in regulating the growth of TAFs using hydrogels with tunable elasticity. These experiments revealed that TAFs from SCC (but not ADC) patients exhibited a marked growth advantage in stiff substrata, and such advantage was associated with increased β1 integrin expression and signaling through FAK. The latter findings revealed for the first time that the aberrant mechanobiology of TAFs is subtype-specific, which may help identify therapeutic strategies against TAFs in each lung cancer subtype.