Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth

Surajit Sinha; Abir Kumar Panda; Rodrigo Xavier das Neves; Zeribe C. Nwosu; Ke Xu; Elke van Beek; Priyanka P. Desai; Sivasish Sindiri; Sruthi Chempati; Kirsten Remmert; Billel Gasmi; Linda Bojmar; Constantinos Zambirinis; Alexander J. Rossi; Reed I. Ayabe; Michael M. Wach; James D. McDonald; Samantha M. Ruff; Emily A. Verbus; Areeba Saif; Alyssa V. Eade; Carolina M. Larrain; Lindsay R. Friedman; Shreya Gupta; Alok Ranjan; Martha E. Teke; Tahsin M. Khan; Tracey Pu; Amber Leila Sarvestani; Carrie E. Ryan; Jacob T. Lambdin; Kenneth Luberice; Stephanie N. Gregory; Stephanie C. Lux; Hanna Hong; Allen J. Luna; Imani A. Alexander; Sarfraz R. Akmal; Shahyan U. Rehman; Ashley Rainey; Todd D. Prickett; Vishal N. Koparde; Samantha Sevilla; Skyler A. Kuhn; King Chan; Zhonghe Sun; Nina Bubunenko; Eileen Li; Cathleen Hannah; Geneti Gaga; Thorkell Andresson; Margaret C. Cam; Xiaolin Wu; Lisa M. Jenkins; Andrew M. Blakely; Jeremy L. Davis; Giorgio Trinchieri; Pankaj K. Singh; James C. Yang; Marina Pasca di Magliano; Costas A. Lyssiotis; Michael B. Yaffe; Ethan M. Shevach; Jonathan M. Hernandez

doi:10.1158/2159-8290.CD-24-1055

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Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth

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Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth

Surajit Sinha, Abir Kumar Panda, Rodrigo Xavier das Neves, Zeribe C. Nwosu, Ke Xu, Elke van Beek, Priyanka P. Desai, Sivasish Sindiri, Sruthi Chempati, Kirsten Remmert, …

Cancer discovery, Vol.15(11), pp.2344-2373

11/03/2025

DOI: 10.1158/2159-8290.CD-24-1055

PMID: 40736016

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Abstract

Expression of IMPACT, a biological inhibitor of GCN1 stress signaling, disrupts metabolic homeostasis and augments tumor immunogenicity to activate innate and adaptive antitumor immune responses in immunotherapy-resistant tumors. Given the propensity of aggressive epithelial tumors to form hepatic metastases, we performed an in vivo cDNA screen using the mouse liver and KRASG12D/TP53R273H pancreatic cells that identified the RNA-binding protein GCN1 as an integral component of hepatic outgrowth. RNAi experiments reveal that GCN1 triggers the integrated stress response (ISR) to activate serine, folate, and methionine biosynthetic pathways together with amino acid transporters, which act in concert to facilitate acquisition of metabolites and to restore redox homeostasis. Alongside the activation of the ISR, we found that GCN1 also functions in the nucleus where it interacts with HNRNPK to suppress the expression of MHC-I molecules and NK ligands. Intriguingly, we identified IMPACT as an endogenous competitive inhibitor of GCN1 that blocks both ISR-dependent metabolic control and disrupts HNRNPK interaction. In doing so, IMPACT enhances tumor immunogenicity to unleash NK cell killing, in addition to sensitizing metastatic tumor cells to immune checkpoint blockade.

Cellular Stress Responses

Epigenetics

Gastrointestinal Cancers

Immunotherapy

Tumor Microenvironment

Details

Title: Subtitle: Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth
Creators: Surajit Sinha - National Cancer Institute
Abir Kumar Panda - National Institutes of Health
Rodrigo Xavier das Neves
Zeribe C. Nwosu - Cornell University
Ke Xu - Boston University
Elke van Beek - Memorial Sloan Kettering Cancer Center
Priyanka P. Desai - National Institutes of Health
Sivasish Sindiri - National Institutes of Health
Sruthi Chempati - National Institutes of Health
Kirsten Remmert - National Institutes of Health
Billel Gasmi - National Institutes of Health
Linda Bojmar - Linköping University
Constantinos Zambirinis - Linköping University
Alexander J. Rossi - Rutgers, The State University of New Jersey
Reed I. Ayabe - University of California, Irvine
Michael M. Wach - Moffitt Cancer Center
James D. McDonald - National Institutes of Health
Samantha M. Ruff - University of Virginia
Emily A. Verbus - Cleveland Clinic
Areeba Saif - National Institutes of Health
Alyssa V. Eade - National Institutes of Health
Carolina M. Larrain - National Institutes of Health
Lindsay R. Friedman - National Institutes of Health
Shreya Gupta - National Institutes of Health
Alok Ranjan - National Institutes of Health
Martha E. Teke - Southwestern Medical Center
Tahsin M. Khan - University of Pittsburgh Medical Center
Tracey Pu - National Institutes of Health
Amber Leila Sarvestani - National Institutes of Health
Carrie E. Ryan - University at Buffalo, State University of New York
Jacob T. Lambdin - George Washington University
Kenneth Luberice - University of Florida Health
Stephanie N. Gregory - Johnson University
Stephanie C. Lux - Northwestern University
Hanna Hong - Johns Hopkins University
Allen J. Luna - Vanderbilt University
Imani A. Alexander - Rutgers, The State University of New Jersey
Sarfraz R. Akmal - Johnson University
Shahyan U. Rehman - Yale New Haven Hospital
Ashley Rainey - National Institutes of Health
Todd D. Prickett - Utrecht University
Vishal N. Koparde - National Cancer Institute
Samantha Sevilla - National Cancer Institute
Skyler A. Kuhn - National Institutes of Health
King Chan - National Cancer Institute
Zhonghe Sun - Leidos (United States)
Nina Bubunenko - Leidos (United States)
Eileen Li - University of Pittsburgh
Cathleen Hannah - National Institutes of Health
Geneti Gaga - National Institutes of Health
Thorkell Andresson
Margaret C. Cam
Xiaolin Wu - Leidos (United States)
Lisa M. Jenkins - National Institutes of Health
Andrew M. Blakely - National Institutes of Health
Jeremy L. Davis - University of Maryland, Baltimore
Giorgio Trinchieri - National Institutes of Health
Pankaj K. Singh - Oklahoma City University
James C. Yang - Brigham and Women's Hospital
Marina Pasca di Magliano
Costas A. Lyssiotis - University of Michigan
Michael B. Yaffe - Center for Cancer Research
Ethan M. Shevach - National Institutes of Health
Jonathan M. Hernandez - National Institutes of Health
Resource Type: Journal article
Publication Details: Cancer discovery, Vol.15(11), pp.2344-2373
DOI: 10.1158/2159-8290.CD-24-1055
PMID: 40736016
NLM abbreviation: Cancer Discov
ISSN: 2159-8274
eISSN: 2159-8290
Number of pages: 30
Alternative title: Expression of IMPACT Abrogates Metastatic Growth
Language: English
Date published: 11/03/2025
Academic Unit: Surgery
Record Identifier: 9985224414202771

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