Tackling molecular targets beyond PD-1/PD-L1: Novel approaches to boost patients' response to cancer immunotherapy

In the new era of immunotherapy, which has changed the clinical oncology practice guidelines, there is a pressing need for finding novel approaches to tune up the clinical outcomes of immunotherapy and extend its benefits to a wider cohort of cancer patients. Several non-classical molecular immune targets beyond PD-1/PD-L1 signaling were shown to be engaged as feedback resistance circuits to shut down the antitumor immune response mediated by the classical immune checkpoint inhibitors. Those include T-cell inducible co-stimulator (ICOS), CD40, CD47, V-domain Ig suppressor of T-cell activation (VISTA), cyclin-dependent kinase (CDK)12, enhancer of Zeste homolog 2 (EZH2), toll-like receptors (TLRs) and OX-40 (CD134). Herein we critically discussed the latest studies concerned with understanding the mechanisms involved in the negative clinical response to classical immunotherapies and strategies to optimize the efficacy of cancer immunotherapy through novel combinatorial approaches.