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

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

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Abstract

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.

Original language	English
Pages (from-to)	2344–2373
Number of pages	29
Journal	Cancer Discovery
Volume	15
Issue number	11
Early online date	30 Sept 2025
DOIs	https://doi.org/10.1158/2159-8290.CD-24-1055
Publication status	Published - 1 Nov 2025

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cd-24-1055Final published version, 24.5 MBLicence: CC BY-NC-ND

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Sinha, S., Panda, A. K., Xavier das Neves, R., Nwosu, Z. C., Xu, K., van Beek, E., Desai, P. P., Sindiri, S., Chempati, S., Remmert, K., Gasmi, B., Bojmar, L., Zambirinis, C., Rossi, A. J., Ayabe, R. I., Wach, M. M., McDonald, J. D., Ruff, S. M., Verbus, E. A., ... Hernandez, J. M. (2025). Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth. Cancer Discovery, 15(11), 2344–2373. https://doi.org/10.1158/2159-8290.CD-24-1055

@article{b9daba71976c49bfb26de19535ea3099,

title = "Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth",

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = nov,

day = "1",

doi = "10.1158/2159-8290.CD-24-1055",

language = "English",

volume = "15",

pages = "2344{\textendash}2373",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

Sinha, S, Panda, AK, Xavier das Neves, R, Nwosu, ZC, Xu, K, van Beek, E, Desai, PP, Sindiri, S, Chempati, S, Remmert, K, Gasmi, B, Bojmar, L, Zambirinis, C, Rossi, AJ, Ayabe, RI, Wach, MM, McDonald, JD, Ruff, SM, Verbus, EA, Saif, A, Eade, AV, Larrain, CM, Friedman, LR, Gupta, S, Ranjan, A, Teke, ME, Khan, TM, Pu, T, Sarvestani, AL, Ryan, CE, Lambdin, JT, Luberice, K, Gregory, SN, Lux, SC, Hong, H, Luna, AJ, Alexander, IA, Akmal, SR, Rehman, SU, Rainey, A, Prickett, TD, Koparde, VN, Sevilla, S, Kuhn, SA, Chan, K, Sun, Z, Bubunenko, N, Li, E, Hannah, C, Gaga, G, Andresson, T, Cam, MC, Wu, X, Jenkins, LM, Blakely, AM, Davis, JL, Trinchieri, G, Singh, PK, Yang, JC, Pasca di Magliano, M, Lyssiotis, CA, Yaffe, MB, Shevach, EM & Hernandez, JM 2025, 'Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth', Cancer Discovery, vol. 15, no. 11, pp. 2344–2373. https://doi.org/10.1158/2159-8290.CD-24-1055

TY - JOUR

T1 - Expression of IMPACT Curtails Metabolic Plasticity and Augments NK Cell Killing to Abrogate Metastatic Growth

AU - Sinha, Surajit

AU - Panda, Abir Kumar

AU - Xavier das Neves, Rodrigo

AU - Nwosu, Zeribe C

AU - Xu, Ke

AU - van Beek, Elke

AU - Desai, Priyanka P

AU - Sindiri, Sivasish

AU - Chempati, Sruthi

AU - Remmert, Kirsten

AU - Gasmi, Billel

AU - Bojmar, Linda

AU - Zambirinis, Constantinos

AU - Rossi, Alexander J

AU - Ayabe, Reed I

AU - Wach, Michael M

AU - McDonald, James D

AU - Ruff, Samantha M

AU - Verbus, Emily A

AU - Saif, Areeba

AU - Eade, Alyssa V

AU - Larrain, Carolina M

AU - Friedman, Lindsay R

AU - Gupta, Shreya

AU - Ranjan, Alok

AU - Teke, Martha E

AU - Khan, Tahsin M

AU - Pu, Tracey

AU - Sarvestani, Amber Leila

AU - Ryan, Carrie E

AU - Lambdin, Jacob T

AU - Luberice, Kenneth

AU - Gregory, Stephanie N

AU - Lux, Stephanie C

AU - Hong, Hanna

AU - Luna, Allen J

AU - Alexander, Imani A

AU - Akmal, Sarfraz R

AU - Rehman, Shahyan U

AU - Rainey, Ashley

AU - Prickett, Todd D

AU - Koparde, Vishal N

AU - Sevilla, Samantha

AU - Kuhn, Skyler A

AU - Chan, King

AU - Sun, Zhonghe

AU - Bubunenko, Nina

AU - Li, Eileen

AU - Hannah, Cathleen

AU - Gaga, Geneti

AU - Andresson, Thorkell

AU - Cam, Margaret C

AU - Wu, Xiaolin

AU - Jenkins, Lisa M

AU - Blakely, Andrew M

AU - Davis, Jeremy L

AU - Trinchieri, Giorgio

AU - Singh, Pankaj K

AU - Yang, James C

AU - Pasca di Magliano, Marina

AU - Lyssiotis, Costas A

AU - Yaffe, Michael B

AU - Shevach, Ethan M

AU - Hernandez, Jonathan M

PY - 2025/11/1

Y1 - 2025/11/1

N2 - 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.

AB - 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.

U2 - 10.1158/2159-8290.CD-24-1055

DO - 10.1158/2159-8290.CD-24-1055

M3 - Article

C2 - 41025961

SN - 2159-8274

VL - 15

SP - 2344

EP - 2373

JO - Cancer Discovery

JF - Cancer Discovery

IS - 11

ER -

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

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