The future of immune checkpoint combinations with tumor-targeted small molecule drugs.

Immune-checkpoint blockade (ICB) has transformed the landscape of cancer treatment. However, there is much to understand around refractory or acquired resistance in patients in order to utilize ICB therapy to its full potential. In this perspective article, we discuss the opportunities and challenges that are emerging as our understanding of immuno-oncology resistance matures. Firstly, there has been remarkable progress made to understand the exquisite overlap between oncogenic and immune signaling pathways. Several cancer-signaling pathways are constitutively active in oncogenic settings and also play physiological roles in immune cell function. A growing number of precision oncology tumor-targeted drugs show remarkable immunogenic properties that might be harnessed with rational combination strategies. Secondly, we now understand that the immune system confers a strong selective pressure on tumors. Whilst this pressure can lead to novel tumor evolution and immune escape, there is a growing recognition of tumor-intrinsic dependencies that arise in immune pressured environments. Such dependencies provide a roadmap for novel tumor-intrinsic drug targets to alleviate ICB resistance. We anticipate that rational combinations with existing oncology drugs and a next wave of tumor-intrinsic drugs that specifically target immunological resistance will represent the next frontier of therapeutic opportunity.