Cancer immunotherapy has emerged as a promising treatment for several advanced highly aggressive cancers for which conventional therapies have failed. Notably, the significant clinical success of immune checkpoint inhibitors confirms that cancer immunotherapy is a breakthrough in cancer treatment that promises turnaround in cancer cure rates. This enthusiastic view has been seriously hampered by clinical observations showing that relatively few number of patients benefit from remarkable and durable clinical remissions, whereas others reap after a short-term benefit or no benefit at all. Several studies claimed that durable clinical remission using immune checkpoint inhibitors is likely dependent on the infiltration of anti-tumor immune cells to the tumor bed. Therefore, the major challenge is to combine immune checkpoint blockades with strategies aiming to drive cytotoxic immune cells into the tumors. However, three major questions arise when designing successful combination approach in cancer immunotherapy which are: i) what to combine? ii) How to combine and iii) when to combine? Preliminary data from our laboratory showed that selective targeting of autophagy in tumor cells lead to inhibition of tumor growth which is associated with an increased infiltration of functional Lymphocyte T-cells, Natural killers and anti-tumor macrophages. This tumor growth blocking effect of targeting autophagy provides a strong rationale for its use as a backbone for combinatorial strategies along with immune checkpoint blockades. This project will evaluate the impact of combining multi-autophagy inhibition approaches with T-cell and macrophage immune checkpoint blockades on tumor growth inhibition of melanoma and breast carcinoma mice models. The impact of the combination schedule on the immune landscape, tumor vasculature, tumor hypoxic status and the cytokine networks will be evaluated. Through its basic research aspect, this project will contribute to understand how a “cold immune desert” tumor microenvironment can be reprogrammed to a “hot receptive” one able to drive cytotoxic immune cells of the innate and adaptive immune system. Through its clinically oriented aspect, this study will provide a cutting edge advances on how cancer immunotherapy based on immune checkpoint blockades can be improved by using combination approaches. It will also allows the establishment of relevant pre-clinical mouse models and provides the proof-of-concept to set-up innovative clinical trials using selective autophagy inhibitor drugs in combination with immune checkpoint blockades.