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2026-04-21 — Seed + landmark pass

This update combines two ingests: (1) a 3-month incremental backfill from Europe PMC (1,000 candidates → 18 extractions), and (2) a curated landmark ingest of 32 foundational PMIDs covering the established pre-2024 literature on ICI resistance.

Structural change: the synthesis was restructured with a visual tier pill on every claim — established / contested / suspected / emerging. The home page and all mechanism pages now carry four buckets (what has held up, where the field has contradicted itself, what's suspected, what's new).

Schema addition: EvidenceTier enum added to scripts/lib/schemas.py and incorporated into ClaimInState. Future synthesis runs will track tiering of every claim.

What's genuinely new this period (emerging)

  • ATOMIC phase 3 (NEJM): adjuvant atezolizumab + mFOLFOX6 in stage III dMMR colon cancer, HR 0.50 PMID 41880612. Extends ICI benefit to adjuvant dMMR; OS not yet mature.
  • KLRG1 as novel inhibitory checkpoint with a new anti-human mAb PMID 41956544. Distinct from the PD-1/CTLA-4/LAG-3/TIM-3 axis.
  • Anti-TIM-3 + anti-PD-1 achieves 52% ORR in PD-1-pretreated classical Hodgkin lymphoma PMID 41963080.
  • TROP2-claudin-7 tight-junction barrier excludes T cells from TNBC PMID 41932810 — reframes TROP2 as barrier-mechanism target.
  • PKMYT1 inhibition activates cGAS-STING in CRPC PMID 41617394. Novel ICI-sensitizer in a stubbornly refractory tumor type.
  • IFN-γ → IRF1 → AGPAT3 axis sensitizes tumors to ferroptosis PMID 41807033 — extends IFN-γ signaling into lipid metabolism.
  • LOAd703 + atezolizumab in anti-PD-1-refractory melanoma restores ICI-responsive signatures PMID 41888981.
  • 8-gene k-TSP + mucinous biomarker identifies dMMR/MSI-H mCRC subgroup for anti-CTLA-4 addition (HR 0.10) PMID 41950572. Retrospective; prospective validation called for.
  • Six spatial niches outperform PD-L1 IHC for neoadjuvant cSCC response PMID 41617396.
  • hMENA TGF-β-driven CAF signature validated against OAK phase III PMID 41592891.

Genuinely surprising / suspected

  • PD-1 protects clonally expanding T cells from restimulation-induced cell death (in vitro) PMID 41748562. If replicated in vivo, complicates the release-the-brakes framing of anti-PD-1.
  • AARS1-mediated PD-L1 K280 lactylation blocks HUWE1 ubiquitination PMID 41864972; paradoxically, exogenous lactate enhanced anti-PD-L1 preclinically — mechanism needs reconciliation.
  • HILPDA-KLF5-palmitoylation at PD-L1 Cys272 PMID 41876831; fenretinide engagement of TRIM21 restores anti-PD-1 efficacy.
  • deltaHED (germline + somatic HLA-I evolutionary divergence) predicts worse PD-1 outcomes despite higher TMB PMID 41601354. Inverts the naïve HED prediction; retrospective.
  • Hypoalbuminemia causally drives ICI resistance via macrophage arginine metabolism PMID 41940988.
  • M2 TAM-PGE2 → TIGIT on PD-1+ CD8+ in MSS CRC PMID 41196020 — specific combinatorial rationale for an indication where PD-1 has consistently failed.

Landmark context added

32 foundational PMIDs integrated into the synthesis, anchoring the established and contested tiers. Highlights:

Contested / under-replicated findings explicitly flagged in the synthesis

  • HLA-I LOH is not deterministic for ICI response (some LOH patients respond)
  • β2M loss does not uniformly prevent response
  • TMB pan-tumor generalization is debated (FDA pan-tumor approval controversial)
  • Microbiome responder taxa do not replicate across geographies (meta-analyses Lee 2022, McCulloch 2022)
  • Akkermansia relationship is non-monotonic (Derosa 2022)
  • Bacteroidales sign-flipped across CTLA-4 vs PD-1 studies
  • TGF-β clinical translation has failed despite strong biology (bintrafusp alfa, galunisertib, NIS793)
  • bTMB prospective validation failed (B-F1RST)
  • PBRM1 LOF in ccRCC did not replicate (Braun 2020)
  • IPRES underperformed as independent predictor
  • KEYNOTE-177 biphasic PFS + failed OS significance
  • IDO + pembrolizumab failed (ECHO-301)
  • WNT/β-catenin clinical signal weaker than mouse biology
  • Snyder 2014 "shared tetrapeptide signature" did not replicate

These are the calibration points most useful for a reader of the resistance literature, and they are now explicit on each mechanism page.