Evidence map›Paper›PMID 42462829›Full record

ArticleGastroenterology2026

A DR5/Ligase 3-mediated feedback loop perpetuates immunogenicity in mismatch repair deficient colorectal cancer.

Suisui Hao, Yoshiaki Sato, Francesca Battaglin, Joanne Xiu, Yi-Jun Wang, Karam Ashouri, Darleny Lizardo, Zhaojin Liu, Xinyan Lu, Matthew Oberley and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Gastroenterology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Suisui HaoDepartment of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Yoshiaki SatoDepartment of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
Francesca BattaglinDepartment of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
Joanne XiuCaris Life Sciences, Phoenix, AZ 85040, USA.
Yi-Jun WangUPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Karam AshouriDepartment of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
Darleny LizardoUPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Zhaojin LiuDepartment of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Xinyan LuDepartment of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Matthew OberleyCaris Life Sciences, Phoenix, AZ 85040, USA.
Robert E SchoenUPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Heinz-Josef LenzDepartment of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
Jian YuDepartment of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Lin ZhangDepartment of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: lzhang24@usc.edu.

Funding

USC/NORRIS COMPREHENSIVE CANCER CENTER (CORE) SUPPORTP30CA014089 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI MYLES G COCKBURN · 1985 to 2026
$181.4M
VECTOR CORE FACILITYP30CA047904 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI JOHN C. BYRD · 1988 to 2026
$158.0M
STING-dependent Intestinal Regeneration upon Radiation InjuryR01CA260900 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI YU, JIAN · 2022 to 2025
$2.5M
Translation addiction and targeting in colon cancerR01CA215481 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI YU, JIAN · 2018 to 2022
$2.3M
Targeting defective necroptosis in colorectal cancerR01CA247231 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ZHANG, LIN · 2020 to 2024
$2.3M
Role of necroptosis in colorectal cancer therapyR01CA236271 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ZHANG, LIN · 2019 to 2023
$2.2M
BET degraders for improving colorectal cancer therapyR01CA248112 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ZHANG, LIN · 2021 to 2025
$2.1M
NCI NIH HHS P30 CA014089NCI NIH HHS P30 CA047904NCI NIH HHS R01 CA215481NCI NIH HHS R01 CA236271NCI NIH HHS R01 CA247231NCI NIH HHS R01 CA248112NCI NIH HHS R01 CA260900
6 · The paper itself

Abstract

BACKGROUND &

aimsColorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) and microsatellite instability (MSI) are believed to be intrinsically immunogenic and respond more favorably to immune checkpoint inhibitor (ICI) therapy. However, a significant fraction of dMMR/MSI CRCs do not respond or eventually develop resistance to ICIs. The mechanisms underlying dMMR/MSI-associated immunogenicity is unclear. The aim of this study was to investigate the role and mechanism of MSI-induced antitumor immunity in CRCs.

methodsWe used transplant syngeneic tumor models, immune cell co-culture assays, and air-liquid interface (ALI) culture of tumor-derived organoids to investigate the mechanism by which dMMR elicits an antitumor immune response. We also analyzed the gene expression databases of CRC cancer patients receiving ICI treatment.

resultsWe found that inactivating Mlh1 causes endoplasmic reticulum (ER) stress and death receptor 5 (Dr5)-mediated apoptosis in syngeneic colorectal tumors. Sustained immune response against Mlh1-deficient tumors requires nuclear Ligase 3 (Lig3)-mediated release of extrachromosomal circular DNAs (eccDNAs) from apoptotic cells. A feedback Dr5/Lig3 amplification loop perpetuates apoptosis and immune cell activation in Mlh1-deficient syngeneic tumors. This feedback mechanism is critical for the response to ICI therapy in mice, which is supported by a significant association between DR5 or LIG3 expression and the efficacy of ICI therapy in cancer patients.

conclusionsOur results reveal a functional link between dMMR and antitumor immunity, which may be useful for improving ICI therapy in tumors with different MMR statuses.

Indexed as

antitumor immunitydMMR colorectal cancereccDNAimmune checkpoint inhibitor

Identifiers

PMID42462829
PMCPMC13502936

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.