HPV-positive HNSCC and Fc-silent PD-1 blockade: a clinical discrepancy that raises next immunological questions.

The recent phase 3 trial of the Fc-silent anti-programmed cell death protein-1 (PD-1) antibody finotonlimab demonstrated promising clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, an unexpected finding emerged: human papillomavirus (HPV)-positive patients-typically responsive to PD-1 blockade-did not appear to benefit, with a subgroup HR favoring the control arm. This clinical discrepancy raises important mechanistic questions. We hypothesize that the abrogation of Fcγ receptor (FcγR)-mediated functions, while designed to preserve PD-1⁺ T cells, may inadvertently attenuate innate immune mechanisms that are especially relevant in virally driven tumors. In immune-inflamed HPV-positive HNSCC, antitumor activity may depend not only on T-cell activation but also on FcγR-dependent myeloid and natural killer cell function. These considerations prompt further evaluation of how Fc engineering may interact with tumor immune contexture, particularly in virally associated cancers. We suggest experimental validation and stratified analysis in future studies to clarify these context-specific effects.