Evidence map›Paper›PMID 41398009›Full record

ArticleScientific reports2025

Statins attenuate PD-L1 sorting to small extracellular vesicles dependent on ubiquitin-like 3 modification.

Hiroshi Ageta, Yoshihisa Shimada, Tadahiro Nagaoka, Kazuki Takenaka, Yusuke Yoshioka, Kohtaro Konno, Ryosuke Amemiya, Kumiko Nagase, Keisuke Hitachi, Takanori Onouchi and 3 more

Abstract read
In one paragraph

Article in Scientific reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed, 1 pooled it
–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

2 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. 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

13 authors.

Hiroshi AgetaDivision for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, 470-1192, Aichi, Japan. hiage@fujita-hu.ac.jp.
Yoshihisa ShimadaDepartment of Surgery, Tokyo Medical University Hospital, Shinjyuku-ku , Tokyo, 160-0023, Japan.
Tadahiro NagaokaDivision for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, 470-1192, Aichi, Japan.
Kazuki TakenakaDivision for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, 470-1192, Aichi, Japan.
Yusuke YoshiokaDepartment of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Shinjyuku-ku, Tokyo, 160-0023, Japan.
Kohtaro KonnoDepartment of Anatomy, Hokkaido University Faculty of Medicine, Sapporo, 060-8638, Japan.
Ryosuke AmemiyaDepartment of Surgery, Tokyo Medical University Hospital, Shinjyuku-ku , Tokyo, 160-0023, Japan.
Kumiko NagaseDepartment of Surgery, Tokyo Medical University Hospital, Shinjyuku-ku , Tokyo, 160-0023, Japan.
Keisuke HitachiDivision for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, 470-1192, Aichi, Japan.
Takanori OnouchiOpen Facility Center, Research Promotion Headquarters, Fujita Health University, Toyoake, 470-1192, Aichi, Japan.
Masahiko WatanabeDepartment of Anatomy, Hokkaido University Faculty of Medicine, Sapporo, 060-8638, Japan.
Takahiro OchiyaDepartment of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Shinjyuku-ku, Tokyo, 160-0023, Japan.
Kunihiro TsuchidaDivision for Therapies Against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, 470-1192, Aichi, Japan. tsuchida@fujita-hu.ac.jp.

Funding

Japan Society for the Promotion of Science 18K07209, 21K07159, 19H05299, 21H00293, 24K10344Japan Society for the Promotion of Science 23K15567Japan Society for the Promotion of Science 24K10059
6 · The paper itself

Abstract

Small extracellular vesicles (sEVs) mediate cell-to-cell communication by carrying RNAs and proteins. Ubiquitin-like 3 (UBL3) functions as a posttranslational modification factor, regulating protein sorting to sEVs. Programmed cell death ligand 1 (PD-L1) binds to programmed cell death 1 (PD-1) on immune cells, suppressing their function. Although immune checkpoint inhibitors, anti-PD-L1 and anti-PD-1 antibodies, have improved cancer treatment, efficacy remains limited (~ 25%). Per recent studies, PD-L1-containing sEVs are elevated in cancer patients, contributing to impaired immunotherapy responses. Herein, we discovered that PD-L1 is modified by UBL3 and that its sorting to sEVs is regulated by UBL3. Furthermore, we found that statins, commonly prescribed for hypercholesterolemia, inhibit UBL3 modification, thereby reducing PD-L1 sorting to sEVs. Among patients with a high tumor proportion score, serum levels of PD-L1-containing sEVs were significantly lower in those using statins. Consistently, bioinformatic analysis revealed that UBL3 and PD-L1 expression levels affect lung cancer survival. Integrating statins into existing combination therapies may therefore offer a promising strategy to enhance immunotherapy efficacy.

Indexed as

B7-H1 AntigenExtracellular VesiclesHydroxymethylglutaryl-CoA Reductase InhibitorsUbiquitinsCell Line, TumorHumansLung NeoplasmsProtein Processing, Post-TranslationalProtein TransportB7-H1 AntigenCD274 protein, humanHydroxymethylglutaryl-CoA Reductase InhibitorsUbiquitinsImmunotherapyPD-L1Posttranslational modificationSmall extracellular vesiclesStatinsUBL3

Identifiers

PMID41398009
PMCPMC12706078

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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.