PDCD1 and neoplasm: Preclinical and mechanistic work with Fc-null anti-PD-1 mAbs further supports this trajectory: Fc-null frameworks prevent FcγR-mediated resistance and deliver more consistent T-cell activation across “hot” and “cold” tumor models than Fc-competent IgG4 S228P backbones, and IgG4-mediated Fc–Fc interactions can dampen ADCC and ADCP by partner antibodies, whereas Fc-null IgG1 and Fc-null IgG4 variants such as penpulimab and tislelizumab avoid these inhibitory Fc–Fc effects; together, these data provide a rationale for Fc-effector–silent frameworks in PD-1 blockade (141, 142).