Adipose-derived mesenchymal stem cells (ADSCs) are well recognized for their immunosuppressive properties. Within the tumor microenvironment, ADSCs can acquire a cancer-associated ADSCs (CA-ADSCs) phenotype that further enhances their tumor-promoting function. Although metformin has been extensively studied for its metabolic and immunomodulatory effects, whether it can reprogram tumor-conditioned ADSCs and thereby attenuate their immunosuppressive activity remains unclear. In the present study, exposure to cancer-conditioned media induced a phenotypic shift in ADSCs toward an inflammatory and immunosuppressive state, characterized by increased expression of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1), which further enhanced the production of inflammatory mediators, including prostaglandin E₂ (PGE₂). Notably, treatment with metformin attenuated these cancer-conditioned media-induced effects. Functionally, soluble factors derived from CA-ADSC promoted CD8⁺ T cell dysfunction, as evidenced by increased apoptosis and expression of the inhibitory receptors PD1 and Tim3, together with reduced cytokine and granzyme B expression. Collectively, these findings indicate that metformin reprograms the response of ADSCs to tumor-derived signals and consequently attenuate their ability to suppress antitumor CD8⁺ T-cell responses.