Emerging Therapeutic Targets and Drug Resistance Mechanisms in Immunotherapy of Hematological Malignancies

Simple Summary Chimeric antigen receptor T (CAR-T) therapy has revolutionized cancer immunotherapy by inducing a durable response in patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). The challenges for cancer immunotherapy concern complex resistance mechanisms; therefore, a very important therapeutic approach is to focus on the development of rational combinations of targeted therapies with non-overlapping toxicities. Recent progress in the development of potential therapeutics has significantly improved anticancer responses, while next-generation CAR-T-cells may overcome current limitations and decrease unwanted side effects in targeting hematological malignancies.Abstract CAR-T cell therapy has revolutionized the treatment of hematological malignancies with high remission rates in the case of ALL and NHL. This therapy has some limitations such as long manufacturing periods, persistent restricted cell sources and high costs. Moreover, combination regimens increase the risk of immune-related adverse events, so the identification new therapeutic targets is important to minimize the risk of toxicities and to guide more effective approaches. Cancer cells employ several mechanisms to evade immunosurveillance, which causes resistance to immunotherapy; therefore, a very important therapeutic approach is to focus on the development of rational combinations of targeted therapies with non-overlapping toxicities. Recent progress in the development of new inhibitory clusters of differentiation (CDs), signaling pathway molecules, checkpoint inhibitors, and immunosuppressive cell subsets and factors in the tumor microenvironment (TME) has significantly improved anticancer responses. Novel strategies regarding combination immunotherapies with CAR-T cells are the most promising approach to cure cancer.