In the tumor microenvironment (TME), tumor cells are constantly evolving to reduce neoantigen generation and the mutational burden to escape the anti-tumor response. This will lower tumor reactivity to the adaptive immune response and give rise to tumor intrinsic factors, such as altered expression of immune regulatory molecules on tumor cells. Tumor-extrinsic factors, such as immunosuppressive cells, soluble suppressive molecules or inhibitory receptors expressed by immune cells will alter the composition and activity of tumor-infiltrating lymphocytes (TILs) (by increasing T regulatory cells:T effector cells ratio and inhibiting T effector cell function) and promote tumor growth and metastasis. Together, these factors limit the response rates and clinical outcomes to a particular cancer therapy. Within the TME, the cross-talks between immune and non-immune cells result in the generation of positive feedback loops, which augment immunosuppression and support tumor growth and survival (termed as tumor-mediated immunosuppression). Cancer immunotherapies, such as immune checkpoint inhibitors (ICIs) and adoptive cell transfer (ACT), have shown therapeutic efficacy in hematologic cancers and different types of solid tumors. However, achieving durable response rates in some cancer patients remains a challenge as a result of acquired resistance and tumor immune evasion. This could be driven by the cellular and molecular suppressive network within the TME or due to the loss of tumor antigens. In this review, we describe the contribution of the immunosuppressive cellular and molecular tumor network to the development of acquired resistance against cancer immunotherapies. We also discuss potential combined therapeutic strategies which could help to overcome such resistance against cancer immunotherapies, and to enhance anti-tumor immune responses and improve clinical outcomes in patients.