GI Oncology Daily Digest

This international multicohort study (1296 real-world AB-real patients + 645 from IMbrave150 and GO30140) clinically validates SITC-defined primary refractoriness (PRef) to first-line atezolizumab + bevacizumab in HCC for the first time. Roughly 40% of patients were primary refractory, and they fared dramatically worse: median OS 7.3 vs 31.5 months in the real-world cohort (p<0.001). Multiparametric profiling (imaging mass cytometry, RNAseq, single-cell) showed PRef tumors are not simply 'cold' — they harbor an actively immunosuppressive microenvironment enriched in CD163+ macrophages and vascular CAFs, with low intrinsic immunogenicity. Conditional inference tree analysis pinpointed IFN-γ signature downregulation combined with NLR≥3 as the strongest determinant of refractoriness, offering a clinically tractable framework for biomarker-stratified trials and myeloid-targeted combinations.

This first-in-human Phase I study tested telisotuzumab adizutecan (Temab-A, ABBV-400) — a c-Met-targeting ADC carrying a topoisomerase-1 inhibitor payload — as monotherapy at 3 mg/kg every 3 weeks in 42 patients with advanced gastric/GEJ adenocarcinoma after 1-2 prior lines. The ORR was 29% with a 71% clinical benefit rate; median DOR 4.2 months, median PFS 4 months, and median OS 5.8 months. Toxicity was meaningful (88% grade ≥3 TEAEs, anemia in 67%), but the safety profile was considered manageable. Critically, exploratory biomarker work showed response enrichment in tumors with higher c-Met protein expression and MET focal amplification — supporting a biomarker-selected development path and combination strategies in 2L+ GEA, a setting with few effective options.

Using whole-genome sequencing of 58 single-cell-derived tumoroids and 18 matched bulk tumors from six patients with metastatic CRC, the authors reconstructed high-resolution phylogenies of how these cancers evolve under treatment pressure. They found pronounced inter- and intra-patient heterogeneity in the burden and spectrum of chemotherapy-induced mutations, preferentially enriched in more proliferative lineages — meaning different co-existing clones accumulate damage at different rates. Late-stage trajectories were strikingly dynamic, featuring complex structural variants, extrachromosomal DNA amplifications, and LINE-1 retrotranspositions, frequently involving cancer driver genes. The work provides a single-cell foundation for understanding acquired resistance and the genomic chaos of advanced CRC.

Tumour-draining lymph nodes (TDLNs) are the immune system's front line against CRC, yet how they become immunosuppressed is poorly understood. Single-cell RNA sequencing of 23 quadruplet-matched samples (primary tumor, adjacent normal, tumor-free and tumor-invaded nodes) from seven patients revealed that tumor-invaded nodes are dominated by SPP1+ macrophage expansion and active regulatory T-cell differentiation niches. Mechanistically, SPP1+ macrophages drove Tregs toward an immunosuppressive CD137+ phenotype through an SPP1-CD44 axis requiring NF-κB1. In murine footpad-popliteal metastasis models, lipid-nanoparticle siSPP1 combined with anti-CD44 antibody synergistically suppressed lymph node metastasis, reduced CD137+ Tregs, and restored CD8+ T-cell function — nominating a druggable axis to disarm nodal immunosuppression in CRC.

This mechanistic study reframes KRAS — pancreatic cancer's central and famously undruggable driver — as a liability that can be turned against the tumor. The authors show oncogenic KRAS activates the cGAS-STING-TBK1 axis, triggering a type I interferon response that, via ISGF3, upregulates necroptosis effectors including MLKL. This primes PDAC cells for necroptotic death when caspase-8 is removed: in genetically engineered mouse models, cancer-cell-specific caspase-8 deletion eliminated most pancreatic precursor lesions. Therapeutically, pharmacologic caspase inhibition reduced tumor burden in aggressive PDAC models and human patient-derived organoids, and a pan-cancer analysis linked necroptosis gene expression to Ras pathway activity and IFN signatures — suggesting relevance beyond pancreas to other IFN-activated, Ras-driven cancers.