The tumor microenvironment (TME) is a dynamic ecosystem, that evolves with the developing tumor to support its growth and metastasis. A key aspect of TME evolution is the recruitment of stromal fibroblasts, carried out via the release of various tumor signals including tumor necrosis factor (TNFα). These tumor signals in turn alter the mechanical properties of the TME as the tumor grows. Because of the important role of stromal cells in supporting tumor progression, new therapies aim to target stromal fibroblasts. However, these therapies have been unsuccessful in part due to the limited understanding of cross-talk between chemical and altered mechanical signaling within stromal fibroblasts. To investigate this, we designed a coculture assay with YFP-TNFα releasing spheroids embedded within collagen gels alongside fibroblasts to mimic the stromal response within the TME. This resulted in the nuclear translocation of p65 in the stromal fibroblasts which was further intensified by the addition of compressive stress. The combination of mechanical and chemical signals led to cytoskeletal disruption and induced a distinct chromatin state in the stromal fibroblasts. These results highlight the important cross-talk between cytokine signaling and mechanical forces on stromal cells within the TME and facilitate the development of a better spheroid model for therapeutic interventions.