We performed proteogenomic characterization of intrahepatic cholangiocarcinoma (iCCA) using paired tumor and adjacent liver tissues from 262 patients. Integrated proteogenomic analyses prioritized genetic aberrations and revealed hallmarks of iCCA pathogenesis. Aflatoxin signature was associated with tumor initiation, proliferation, and immune suppression. Mutation-associated signaling profiles revealed that TP53 and KRAS co-mutations may contribute to iCCA metastasis via the integrin-FAK-SRC pathway. FGFR2 fusions activated the Rho GTPase pathway and could be a potential source of neoantigens. Proteomic profiling identified four patient subgroups (S1-S4) with subgroup-specific biomarkers. These proteomic subgroups had distinct features in prognosis, genetic alterations, microenvironment dysregulation, tumor microbiota composition, and potential therapeutics. SLC16A3 and HKDC1 were further identified as potential prognostic biomarkers associated with metabolic reprogramming of iCCA cells. This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in iCCA.

Comment in Nat Rev Drug Discov. 2022 Jan;21(1):17. Nat Rev Immunol. 2022 Jan;22(1):4-5. Nat Rev Cancer. 2022 Feb;22(2):69.

Comment in Cancer Cell. 2022 Jan 10;40(1):11-13.

Functional precision medicine is a strategy whereby live tumor cells from affected individuals are directly perturbed with drugs to provide immediately translatable, personalized information to guide therapy. The heterogeneity of human cancer has led to the realization that personalized approaches are needed to improve treatment outcomes. Precision oncology has traditionally used static features of the tumor to dictate which therapies should be used. Static features can include expression of key targets or genomic analysis of mutations to identify therapeutically targetable "drivers." Although a surprisingly small proportion of individuals derive clinical benefit from the static approach, functional precision medicine can provide additional information regarding tumor vulnerabilities. We discuss emerging technologies for functional precision medicine as well as limitations and challenges in using these assays in the clinical trials that will be necessary to determine whether functional precision medicine can improve outcomes and eventually become a standard tool in clinical oncology.

Comment on Nature. 2021 Dec;600(7888):319-323.

Comment in Cancer Cell. 2022 Mar 14;40(3):231-232. Signal Transduct Target Ther. 2022 Mar 3;7(1):68.

Comment in Cancer Cell. 2022 Jan 10;40(1):14-16.

Anti-COVID-19 immunity dynamics were assessed in patients with cancer in a prospective clinical trial. Waning of immunity was detected 4-6 months post-vaccination with significant increases in anti-spike IgG titers after booster dosing, and 56% of seronegative patients seroconverted post-booster vaccination. Prior anti-CD20/BTK inhibitor therapy was associated with reduced vaccine efficacy.

Comment on Nature. 2021 Nov;599(7885):477-484.

In this issue of Cancer Cell, Li et al. show that histamine released in allergic reactions and from tumor cells attenuates immunotherapy response. Histamine H1-receptor (H1R) signaling induces an M2-like phenotype in tumor-associated macrophages and increases VISTA expression, suppressing CD8+ T cell function. Antihistamines reverse these effects and improve the efficacy of immunotherapy.

Comment on Cancer Cell. 2022 Jan 10;40(1):53-69.e9.

Comment on Cancer Cell. 2022 Jan 10;40(1):88-102.e7.

Comment on Nature. 2021 Nov;599(7885):471-476.

Author information: (1)Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Center for the AIDS Programme of Research in South Africa, Durban, South Africa. (2)Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA. (3)Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. (4)Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. (5)Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. (6)Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: aiafrate@partners.org.