An Endocytic Checkpoint Controls Macrophage PD-1 Function and Immunotherapy Fate

Responses to PD1 blockade span durable tumor control to hyperprogressive disease (HPD), yet innate immune mechanisms governing these extremes remain undefined. Here we integrate a macrophage systems atlas (>12,500 transcriptomes) with single-cell profiles from >1,000 anti PD1 treated patients, to identify CCDC88A (GIV) as a macrophage-intrinsic determinant of durable response versus HPD. GIV loss increases PD1 surface retention, suppresses phagocytosis, and accelerates tumor growth across murine models, human macrophages, and patient-derived organoids. Myeloid-specific GIV deletion converts PD1 blockade from tumor-restraining to tumor-accelerating by reprogramming macrophages toward HPD-like states. Mechanistically, GIV engages a conserved TIR-like [TILL] motif within the PD1 cytoplasmic tail to drive dynamin-dependent endocytosis, coupling innate immune signaling logic to checkpoint receptor trafficking. Pharmacologic disruption of this axis phenocopies GIV loss, revealing an endocytic vulnerability that undermines checkpoint efficacy and triggers accelerated growth at relapse. These findings define PD1 routing, rather than ligand-binding, as a macrophage-encoded checkpoint governing antitumor immunity.