In conclusion, CD38 upregulation after IC blockade therapy may contribute to the development of hyperprogression through the release of high levels of adenosine into the TME and the consequent activation of the ADORA2a pathway, which may lead to tumor insensitivity to IFN-γ action, to the downregulation of p53 with consequent tumor growth, and to strong immunosuppression. Here, TP53 is linked to neoplasm.