Abstract: T-cell-oriented cancer immunotherapy, most triumphed by immune checkpoint blockade (ICB) and CAR-T therapies, has transformed the cancer treatment landscape and benefited many patients. However, de novo and acquired resistance to these therapies remains a significant challenge. Our recent works illuminate a number of key tumor-immune crosstalk mechanisms in prostate cancer and breast cancer, where both cancer-cell-intrinsic and -extrinsic pathways contribute to the formation of an immunosuppressive microenvironment, suggesting a concerted targeting strategy is required to overcome immunosuppression and enable immunotherapy efficacy. We identified emerging strategies, including molecularly targeted therapy and dietary interventions. The use of single-cell technologies greatly facilitates understanding the immunocyte changes in response to the experimental therapeutics and helps guide the following steps to improve the efficacy further. The goal of our research is ultimately tipping the survival curves to a complete “flat tail” – the dream of cancer immunotherapy.