Abstract <p>Obesity is a global pandemic representing a significant public health threat, with a rising number of affected individuals and numerous associated co-morbidities, including cancer. In obese cancer patients, higher mortality rates are usually observed compared to normal weight/lean individuals. The imbalanced metabolic asset of obese patients fosters tumor growth and its progression by impacting not only on cancer cells, but also affecting their cross-talk with the tumor microenvironment, which represents a relevant and multifaceted player in disease progression. Herein, we deliver a detailed overview of certain peculiar players implicated in the reprogramming of the tumor microenvironment during obesity toward disease evolution. We highlight the key metabolic, molecular and cellular players that co-opt cancer cells and their microenvironment to foster disease progression. We emphasize the role of certain hormones and growth factors-dependent pathways (Insulin/IGF signaling system and VEGF/VEGFR axis) together with inflammatory pathways (RAGE signaling system) in triggering microenvironmental-dependent evolution of neoplastic disease during obesity. Finally, we underline current pitfalls and envisage innovative tools and future directions for better investigating tumor progression in obesity.</p> Graphical abstract <p></p>