Bypassing anti-PD-(L)1 therapy: Mechanisms and management strategies

Resistance to immune checkpoint inhibitors (ICIs) is a major issue of the current era in cancer immunotherapy. Immune evasion is a multi-factorial event, which occurs generally at a base of cold immunity. Despite advances in the field, there are still unsolved challenges about how to combat checkpoint hijacked by tumor cells and what are complementary treatment strategies to render durable anti-tumor outcomes. A point is that anti-programed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) is not the solo path of immune escape, and responses in many types of solid tumors to the PD-1/PD-L1 inhibitors are not satisfactory. Thus, seeking mechanisms inter-connecting tumor with its immune ecosystem nearby unravel more about resistance mechanisms so as to develop methods for sustained reinvigoration of immune activity against cancer. In this review, we aimed to discuss about common and specific paths taken by tumor cells to evade immune surveillance, describing novel detection strategies, as well as suggesting some approaches to recover tumor sensitivity to the anti-PD-(L)1 therapy based on the current knowledge.