Evidence map›Paper›PMID 42707650›Full record

ArticleTheranostics2026

Targeting USP22 reprograms the tumor microenvironment and sensitizes KRAS/p53-driven lung cancer to anti-PD-1 immunotherapy.

Keqiang Zhang, Ching Ouyang, Jonathan Castillo, Jinhui Wang, Walter Tsark, Yuanyuan Gao, Wendong Li, Minxiao Yang, Aimin Li, Britney Oeung and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Theranostics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

16 authors.

Keqiang ZhangDivision of Thoracic Surgery, City of Hope National Medical Center, Duarte, California, USA.
Ching OuyangIntegrative Genomics Core, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Jonathan CastilloDepartment of Integrative Translational Sciences, City of Hope National Medical Center, Duarte, CA, USA.
Jinhui WangIntegrative Genomics Core, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Walter TsarkTransgenic/Knockout Program, City of Hope National Medical Center, Duarte, CA, USA.
Yuanyuan GaoDivision of Thoracic Surgery, City of Hope National Medical Center, Duarte, California, USA.
Wendong LiDivision of Thoracic Surgery, City of Hope National Medical Center, Duarte, California, USA.
Minxiao YangDepartment of Integrative Translational Sciences, City of Hope National Medical Center, Duarte, CA, USA.
Aimin LiPathology Core of Shared Resources, City of Hope National Medical Center, Duarte, CA, USA.
Britney OeungImmuno-Oncology Facility, Department of Immune-Oncology, City of Hope National Medical Center, Duarte, CA, USA.
Colt EgelstonImmuno-Oncology Facility, Department of Immune-Oncology, City of Hope National Medical Center, Duarte, CA, USA.
Jun WuDivision of Comparative Medicine, City of Hope National Medical Center, Duarte, CA, USA.
Mahima RaulDivision of Thoracic Surgery, City of Hope National Medical Center, Duarte, California, USA.
Leonidas ArvanitisDepartment of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
Crystal MarconettDepartment of Integrative Translational Sciences, City of Hope National Medical Center, Duarte, CA, USA.
Dan J RazDivision of Thoracic Surgery, City of Hope National Medical Center, Duarte, California, USA.

Funding

Transgenic Mouse FacilityP30CA033572 · NCI · CITY OF HOPE/BECKMAN RESEARCH INSTITUTE · PI John Charles Williams · 1985 to 2026
$86.3M
Elucidating the Cellular Origins of lung adenocarcinomaR01CA262258 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Crystal Nicole Marconett · 2023 to 2026
$1.4M
NCI NIH HHS P30 CA033572NCI NIH HHS R01 CA262258
6 · The paper itself

Abstract

Rationale: Ubiquitin-specific peptidase 22 (USP22), a deubiquitinase and component of the "Death-from-Cancer" 11-gene signature, is overexpressed in multiple malignancies and linked to recurrence, therapy resistance, and poor prognosis. Its role in KRAS/p53-driven lung cancer and the response to immune checkpoint inhibitors (ICIs) remains poorly defined. Here, we investigated USP22 as a potential therapeutic target in KRAS/p53-driven lung cancer. Methods: A conditional Usp22 knockout (Usp22-KO) was generated in the KRAS Results: USP22 was highly expressed in early-stage KRAS/p53-driven mouse lung cancers and strongly correlated with proliferation marker Ki67. Usp22 deletion suppressed cancer growth, prolonged survival, and promoted cancer differentiation. Spatial transcriptomics and mIF revealed reduced CD206+ M2 macrophages, myeloid-derived suppressor cells (MDSCs), TGF-β1, and angiogenesis, along with increased functional CD8+ T cells. Mechanistically, USP22 regulated gene expression and protein stability, reducing c-Myc, PD-L1, TGF-β1, and SPARC upon Usp22 loss. Compared with KP cancer, KPU- and SPARC-knockdown KP cancers showed reduced macrophage chemotaxis and impaired basal- and TGF-β1-induced M2 polarization of RAW264.7 cells, suggesting that TGF-β1 and SPARC downregulation partially contributes to decreased M2 macrophage infiltration in KPU- cancers. Notably, Usp22 loss enhanced the efficacy of anti-PD-L1 and anti-PD-1 therapies in orthotopic and subcutaneous KP lung cancer models, respectively. USP22 and SPARC expression were also strongly correlated in human lung cancers. Conclusions: USP22 promotes progression and immune evasion in KRAS/p53-driven lung cancer. Targeting USP22 reprograms the TME, suppresses oncogenic signaling, and sensitizes tumors to ICI, establishing USP22 as a promising therapeutic target.

Indexed as

Immune Checkpoint InhibitorsLung NeoplasmsProto-Oncogene Proteins p21(ras)Tumor MicroenvironmentTumor Suppressor Protein p53Ubiquitin ThiolesteraseAnimalsCell Line, TumorGene Expression Regulation, NeoplasticHumansImmunotherapyMiceMice, KnockoutProgrammed Cell Death 1 ReceptorHras protein, mouseImmune Checkpoint InhibitorsProgrammed Cell Death 1 ReceptorProto-Oncogene Proteins p21(ras)Trp53 protein, mouseTumor Suppressor Protein p53Ubiquitin ThiolesteraseUsp22 protein, humanUSP22 protein, mouseanti-PD-1 therapyimmune checkpoint inhibitors (ICI)KRAS/p53-driven lung cancertumor microenvironment (TME)Ubiquitin-specific peptidase (USP22)

Identifiers

PMID42707650
PMCPMC13549226

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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 Socratic graph.