Driven by hypoxia and inflammatory cytokines, PD-L1 is overexpressed in the TME, along with an elevated expression of PD-1 on tumor-infiltrating lymphocytes, resulting in the disruption of the cancer-immunity cycle.14 Due to the well-established role of PD-1 on tumor-infiltrating cytotoxic T cells and conventional CD4 T cells, we designated this pathway, canonical PD-1 signaling (figure 1). Here, CD4 is linked to cancer.