Regorafenib, nivolumab and chemotherapy reshape the gastric tumor microenvironment, exposing resistance targets
- A phase 1b/2 trial tested first-line regorafenib, the PD-1 antibody nivolumab and chemotherapy in mismatch repair–proficient advanced gastric cancer; the primary end point was met, with a high objective response rate.
- Single-cell RNA and T cell receptor sequencing of serial biopsies showed more tumor-reactive CD8 T cells and proinflammatory macrophages, and fewer suppressive regulatory T cells, CAFs, pericytes and tip cells.
- At progression, regulatory T cells reexpanded and lipid-associated macrophage subsets emerged. In mouse resistance models, anti-CCR8 or anti-TREM2 antibodies with PD-1 blockade restored antitumor immunity.
💡 Points Based on the abstract
Which arm is doing the work? Regorafenib's VEGFR and CSF1R inhibition plausibly explains the drop in pericytes, tip cells and suppressive myeloid cells, but a single-arm combination can't separate that from chemo or PD-1 effects. The CCR8 and TREM2 mouse data are hypothesis-grade: syngeneic models rarely recapitulate acquired resistance, and anti-CCR8 depleting Tregs raises tumor-selectivity and on-target safety questions in humans.