This review focuses on significant advances in the nonclassical PD-1/PD-L1 axis, summarizes and discusses the roles of T-cell-intrinsic PD-L1 and myeloid/tumor cell-intrinsic PD-1 in cancer progression and the complex implications for anti-PD efficacy, hoping to inspire more rational anti-PD drug design and combination strategies. The gene discussed is CD274; the disease is cancer.