Abstract How intracellular proteins, normally hidden from the immune system, become targets of tumor-associated antibody responses remains unresolved, as does the function of such autoantibodies encoded by tumor-infiltrating B cells (TIL-Bs). Using monoclonal antibodies (mAbs) cloned from TIL-Bs in a spontaneous hepatocellular carcinoma (HCC) model, we define a class of antigens: secreted intracellular antigens (SICAs). Tumors co-opt upregulated autophagy to release cytosolic proteins, exemplified by ALDH1L1, through HSP90-mediated autophagy-dependent unconventional secretion. The resulting autoantibodies form immune complexes at the tumor site, where the SICA is locally available, recruiting and reprogramming neutrophils into tumor-associated neutrophils that drive tumor progression. Both neutrophil depletion and loss of Fcγ receptor binding abolish this effect. Autophagy-mediated SICA secretion and the corresponding autoantibody response are conserved in HCC patients and extend to lung, breast and cervical cancers. Tumors thus reshape their secretome to hijack humoral immunity, highlighting the SICA–autoantibody–FcγR axis as a potential therapeutic target.
Summary: Although studies of microbiota in hepatocellular carcinoma (HCC) and possible involvement of the gut–liver axis are of significant interest, the origin and functional role of the liver and intratumoral microbiota in HCC have remained unclear. Liu and colleagues show that gut pathobionts, in particular Bacteroides fragilis, translocate through the gut–liver axis, colonize and reshape the intrahepatic microbiome, and promote HCC through a distinct mechanism in which bacterial enolase binds hepatocyte vimentin, revealing potential therapeutic opportunities. See related article by Liu et al., p. 2392
Summary: In this issue, two studies establish KRASG13C as a directly targetable oncoprotein in non–small cell lung cancer (NSCLC) while revealing distinct dependence of codon 13–mutant NSCLC on wild-type (WT) RAS and enhanced sensitivity to standard-of-care chemotherapy. A third study highlights rewired oncogenic signaling through WT RAS as a therapeutically tractable mechanism of resistance to KRASG12C inhibitors in the context of acquired oncogenic kinase fusions. See related article by Scaparone et al., p. 2242 See related article by Seamon et al., p. 2256 See related article by McDaid et al., p. 2274
Summary: A large proportion of pediatric sarcomas are driven by neomorphic transcription factors that are challenging therapeutic targets. In this issue, two independent studies identify CDK8 as a shared therapeutic vulnerability in pediatric fusion oncoprotein–driven sarcomas and reveal that CDK8 inhibitors disrupt oncogenic transcriptional programs through an unexpected gain-of-function mechanism involving Mediator complex trapping on chromatin. See related article by Zhang et al., p. 2344 See related article by McGinnis et al., p. 2366
