---
title: "SSRIs and Immune Checkpoint Inhibitors in Solid Tumors: Target Trial Emulation and Pan‑Cancer Tran"
id: "plos-medicine-0-selective-serotonin-reuptake-inhibitors-and-immune-checkpoint-blockade-in-solid"
canonical_url: "https://medichelpline.com/clinical-feed/plos-medicine-0-selective-serotonin-reuptake-inhibitors-and-immune-checkpoint-blockade-in-solid"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PLOS Medicine"
source_url: "https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262"
published_at: "2026-09-29T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# SSRIs and Immune Checkpoint Inhibitors in Solid Tumors: Target Trial Emulation and Pan‑Cancer Tran
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-medicine-0-selective-serotonin-reuptake-inhibitors-and-immune-checkpoint-blockade-in-solid
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PLOS Medicine
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262)
- **Published At:** 2026-09-29T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This study emulated a target trial using the TriNetX federated electronic health record network to compare outcomes for patients with a solid tumor and a depressive or anxiety disorder who were receiving immune checkpoint inhibitors (ICIs) and either a **selective serotonin reuptake inhibitor (SSRI)** or a benzodiazepine (BZD) at ICI initiation. - Eligibility required adult patients with a first ICI administration between 2015 and 2025 and a recorded depressive or anxiety disorder within 365 days; exposure was defined by an active SSRI or BZD prescription overlapping the index date or starting within the prior 90 days. - Propensity score matching (1:1) on 49 baseline covariates produced 1,567 matched pairs (3,134 patients) for primary analyses. - The primary outcome was 2‑year overall survival. SSRI use was associated with lower 2‑year all‑cause mortality (23.5% vs 34.4%; HR 0.627, 95% CI 0.549–0.716; p < 0.001). An E‑value was reported (2.57) to quantify robustness to unmeasured confounding. - Secondary findings: composite **immune-related adverse events (irAEs)** were more frequent with SSRI use (HR 1.162; 95% CI 1.039–1.299; p = 0.008), driven mainly by thyroid dysfunction (HR 1.199; 95% CI 1.053–1.366; p = 0.006); no increases in hepatitis, pneumonitis, or colitis were observed. - SSRI users had fewer newly coded distant metastases (HR 0.629; 95% CI 0.487–0.811; p < 0.001) and fewer referrals to hospital and palliative care in unmatched summaries; three negative control outcomes (nephrolithiasis, cholelithiasis, cataract) were null. - All five individually analyzable SSRIs were each associated with lower mortality (HR range 0.61–0.71). - Parallel transcriptomic analyses used TCGA bulk tumor data (8,272 samples across 20 tumor types) and found that **SLC6A4** expression was inversely correlated with T‑cell inflammation in 13 of 20 cancers; organ‑level expression patterns aligned with organ‑specific irAE patterns. - Key limitations: residual confounding (notably missing performance status) and differences in indications for BZD versus SSRI prescribing; TCGA analyses used bulk tissue from patients not treated with ICIs and cannot localize SLC6A4 to specific cell types or demonstrate that SSRIs alter the tumor microenvironment. - Authors conclude that associations and transcriptomic findings support biological plausibility and warrant prospective randomized evaluation of **SSRI repurposing** as an ICI adjuvant.
## Clinical Analysis & Structured Key Points
[ Skip to main content ](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#main-content) Advertisement * [plos.org](https://plos.org/) * [Create account](https://community.plos.org/registration/new) * [Sign in](https://journals.plos.org/user/secure/login?page=%2Fplosmedicine%2Farticle%3Fid%3D10.1371%2Fjournal.pmed.1005262) * * About * Browse * Publish * [](https://journals.plos.org/plosmedicine/ "PLOS Medicine") * Search [advanced search](https://journals.plos.org/plosmedicine/search) * 0 [Save](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005262#savedHeader) [Total Mendeley and Citeulike bookmarks.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005262#savedHeader) * 0 [Citation](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005262#citedHeader) [Paper's citation count computed by Dimensions.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005262#citedHeader) * 10 [View](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005262#viewedHeader) [PLOS views and downloads.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005262#viewedHeader) * 0 [Share](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005262#discussedHeader) [Sum of Facebook, Twitter, Reddit and Wikipedia activity.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005262#discussedHeader) Open Access Peer-reviewed Research Article # Selective serotonin reuptake inhibitors and immune checkpoint blockade in solid tumors: A target trial emulation with pan-cancer transcriptomic analyses * Po-Huang Chen, Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing Affiliations Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan, Department of Oncology, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-0280-6417 ](https://orcid.org/0000-0002-0280-6417 "ORCID Registry") ⨯ * Ming-Shen Dai , Roles Conceptualization, Resources, Supervision, Writing – review & editing * E-mail: dms1201@gmail.com (M-SD); xsai4295@gmail.com (H-JJ); drleechohao@gmail.com (C-HL) Affiliations Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan, Department of Oncology, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-3953-5243 ](https://orcid.org/0000-0002-3953-5243 "ORCID Registry") ⨯ * Mao-Hsuan Huang, Roles Resources, Writing – review & editing Affiliation Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-7970-3758 ](https://orcid.org/0000-0002-7970-3758 "ORCID Registry") ⨯ * Hsin-Yu Chen, Roles Resources, Writing – review & editing Affiliation Department of Family Medicine, Chi Mei Medical Center, Tainan, Taiwan [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0007-0552-569X ](https://orcid.org/0009-0007-0552-569X "ORCID Registry") ⨯ * Li-Ting Kao, Roles Data curation, Formal analysis, Writing – review & editing Affiliations Graduate Institute of Life Sciences, National Defense Medical University, Taipei, Taiwan, School of Pharmacy, National Defense Medical University, Taipei, Taiwan, Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0003-0692-7408 ](https://orcid.org/0000-0003-0692-7408 "ORCID Registry") ⨯ * Tina Yi-Jin Hsieh, Roles Resources, Writing – review & editing Affiliation Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-6296-0689 ](https://orcid.org/0000-0001-6296-0689 "ORCID Registry") ⨯ * Hong-Jie Jhou , Roles Data curation, Formal analysis, Writing – review & editing * E-mail: dms1201@gmail.com (M-SD); xsai4295@gmail.com (H-JJ); drleechohao@gmail.com (C-HL) Affiliation Neurological Institute, Changhua Christian Hospital, Changhua, Taiwan [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0003-3304-4643 ](https://orcid.org/0000-0003-3304-4643 "ORCID Registry") ⨯ * Cho-Hao Lee Roles Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing * E-mail: dms1201@gmail.com (M-SD); xsai4295@gmail.com (H-JJ); drleechohao@gmail.com (C-HL) Affiliations Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan, Department of Oncology, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-6061-5168 ](https://orcid.org/0000-0002-6061-5168 "ORCID Registry") ⨯ # Selective serotonin reuptake inhibitors and immune checkpoint blockade in solid tumors: A target trial emulation with pan-cancer transcriptomic analyses * Po-Huang Chen, * Ming-Shen Dai, * Mao-Hsuan Huang, * Hsin-Yu Chen, * Li-Ting Kao, * Tina Yi-Jin Hsieh, * Hong-Jie Jhou, * Cho-Hao Lee ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: September 29, 2026 * * [Article](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262) * [Authors](https://journals.plos.org/plosmedicine/article/authors?id=10.1371/journal.pmed.1005262) * [Metrics](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1005262) * [Comments](https://journals.plos.org/plosmedicine/article/comments?id=10.1371/journal.pmed.1005262) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pmed.1005262) * [Peer Review](https://journals.plos.org/plosmedicine/article/peerReview?id=10.1371/journal.pmed.1005262) * [Abstract](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#abstract0) * [Author summary](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#abstract1) * [Introduction](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#sec004) * [Methods](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#sec005) * [Results](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#sec013) * [Discussion](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#sec019) * [Supporting information](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#sec021) * [Acknowledgments](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#ack) * [References](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#references) * [Reader Comments](https://journals.plos.org/plosmedicine/article/comments?id=10.1371/journal.pmed.1005262) * [Figures](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262) [?](https://journals.plos.org/plosmedicine/s/accepted-manuscripts#loc-early-version) ## This is an uncorrected proof. ## Abstract ### Background Preclinical evidence identifies the serotonin transporter (SERT, encoded by SLC6A4) as an immune checkpoint on CD8+ T cells, with selective serotonin reuptake inhibitors (SSRIs) enhancing antitumor immunity in synergy with anti-programmed cell death protein 1 (anti-PD-1) therapy. Whether this translates into clinical benefit for patients receiving immune checkpoint inhibitors (ICIs) is unknown. Using a target trial emulation framework, we compared outcomes between SSRI users and benzodiazepine (BZD) users among patients with a solid tumor and depression or anxiety who were receiving an ICI. Separately, in The Cancer Genome Atlas (TCGA), which covers a different set of patients, we examined how SLC6A4 expression related to tumor immune-cell infiltration across cancers. ### Methods and findings We emulated a target trial in the TriNetX federated electronic health record network (over 187 million patients), comparing SSRI with BZD treatment at first ICI administration under an intention-to-treat-analogue estimand. Eligible patients were adults with a solid tumor, a first ICI administration between 2015 and 2025, and a depressive or anxiety disorder recorded within the prior 365 days. Exposure required an active SSRI or BZD prescription overlapping the index date or starting within the preceding 90 days, not necessarily on that date. The primary outcome was 2-year overall survival; 20 secondary outcomes across 4 mechanistic pathways were prespecified. Propensity score matching (1:1) on 49 baseline covariates yielded 1,567 pairs. Estimates are hazard ratios (HRs) with 95% confidence intervals (CIs). Transcriptomic analyses used TCGA (8,272 tumor samples from 8,172 patients, 20 tumor types). Among 3,134 matched patients, SSRI use was associated with lower 2-year all-cause mortality (23.5% versus 34.4%; HR 0.627; 95% CI [0.549, 0.716]; _p_ 0.09). Newly coded distant metastases were less frequent in the SSRI group (HR 0.629; 95% CI [0.487, 0.811]; _p_ 0.76). All 5 individually analyzable SSRIs were associated with lower mortality (HR range 0.61 to 0.71). In TCGA, SLC6A4 expression was inversely correlated with T-cell inflammation in 13 of 20 cancer types, and this organ-level pattern matched that of organ-specific irAEs. The main limitation is residual confounding: performance status, a clinician's rating of everyday functional ability that strongly predicts cancer survival, is not recorded in the network, and BZDs are prescribed in different circumstances from SSRIs, so the groups may differ in ways matching cannot capture. The TCGA analyses used bulk tumor tissue from patients not treated with ICIs, so they cannot localize SLC6A4 to particular cells or show that SSRIs alter the tumor microenvironment. ### Conclusions In this study, SSRI use was associated with lower mortality and organ-selective immune activation compared with BZD use among ICI-treated patients with psychiatric comorbidity. Transcriptomic evidence supports biological plausibility. These findings warrant prospective evaluation of SSRI repurposing as an ICI adjuvant. ## Author summary ### Why was this study done? * Depression and anxiety affect 20–40% of people with cancer who receive immunotherapy, and the psychiatric medicines prescribed for them differ in how they act on the immune system. * Laboratory studies have shown that the serotonin transporter acts as a brake on cancer-fighting T cells, and that selective serotonin reuptake inhibitors (SSRIs) release that brake in mice treated with immunotherapy. * It was not known whether the choice between an SSRI and a benzodiazepine, the other psychiatric medicine commonly prescribed in this setting, is related to how people fare on immunotherapy. ### What did the researchers do and find? * Using electronic health records from a large international network, we compared 1,567 people taking an SSRI with 1,567 people taking a benzodiazepine, all of whom had a solid tumor and depression or anxiety and were beginning immunotherapy, matched on 49 clinical characteristics. * Over 2 years, 23.5% of the SSRI group died compared with 34.4% of the benzodiazepine group, and the SSRI group also had fewer newly recorded secondary tumors and fewer referrals to hospital and to palliative care. * The SSRI group had more immune-related side effects overall, almost entirely thyroid problems, with no increase in inflammation of the liver, lungs, or bowel, and in tumor tissue from more than 8,000 cancers in a separate group of patients, higher activity of the serotonin transporter gene went with fewer immune cells inside the tumor. ### What do these findings mean? * SSRIs, which are already widely prescribed to people with cancer, were associated with better outcomes during immunotherapy, and both the pattern of side effects and the tumor gene activity data are consistent with an effect on the immune system; a randomized trial is needed to test this directly. * Because people were not randomly assigned to receive one medicine or the other, these results show an association and cannot show that SSRIs caused the better outcomes. * The records do not capture how well or unwell a person was when treatment started, and benzodiazepines are often given at times of acute distress or worsening illness, so part of the difference may reflect how ill people were rather than the medicine itself. ## Figures ![Fig 5](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.g005) ![Fig 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.g001) ![Fig 2](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.g002) ![Table 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.t001) ![Fig 3](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.g003) ![Table 2](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.t002) ![Fig 4](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.g004) ![Fig 5](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.g005) ![Fig 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.g001) ![Fig 2](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.g002) ![Table 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1005262.t001) **Citation:** Chen P-H, Dai M-S, Huang M-H, Chen H-Y, Kao L-T, Hsieh TY-J, et al. (2026) Selective serotonin reuptake inhibitors and immune checkpoint blockade in solid tumors: A target trial emulation with pan-cancer transcriptomic analyses. PLoS Med 23(9): e1005262. https://doi.org/10.1371/journal.pmed.1005262 **Academic Editor:** Tessho Maruyama, University of the Ryukyus: Ryukyu Daigaku, JAPAN **Received:** March 19, 2026; **Accepted:** August 27, 2026; **Published:** September 29, 2026 **Copyright:** © 2026 Chen et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** The clinical data underlying this study were obtained from the TriNetX Global Collaborative Network ( ). TriNetX operates as a federated network in which patient-level records remain within each participating health care organization and cannot be exported, shared, or transferred outside the platform under institutional data use agreements, so the authors are not permitted to redistribute patient-level data. The authors accessed the platform under their institution’s standard TriNetX license and had no special access privileges. Any qualified investigator can obtain the same access by applying directly to TriNetX ( ) and can thereby reproduce the aggregate analyses reported here. All aggregate values underlying the findings, including the event counts, risks, hazard ratios, confidence intervals, and _p_ values behind every figure and table of the matched analyses, are reported within this article and its [Supporting information](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#sec021) files; for the unmatched before-matching analyses in [S21 Table](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#pmed.1005262.s031), hazard ratios, confidence intervals, and _p_ values are reported. The transcriptomic data are publicly available from the National Cancer Institute Genomic Data Commons ( ) as the following 20 TCGA projects: TCGA-BLCA, TCGA-BRCA, TCGA-CESC, TCGA-COAD, TCGA-ESCA, TCGA-HNSC, TCGA-KICH, TCGA-KIRC, TCGA-KIRP, TCGA-LIHC, TCGA-LUAD, TCGA-LUSC, TCGA-PAAD, TCGA-PRAD, TCGA-READ, TCGA-SARC, TCGA-SKCM, TCGA-STAD, TCGA-THCA, and TCGA-UCEC. All analysis code for the transcriptomic analyses, together with the derived data files that underlie Figs 5A, [S3](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#pmed.1005262.s007), and [S5](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#pmed.1005262.s009) is publicly available in the GitHub repository and is permanently archived in Zenodo ( ). The values behind [Fig 5B](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#pmed-1005262-g005) and [5C](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#pmed-1005262-g005) are reproducible from the released analysis code and the public Genomic Data Commons inputs, and the organ-level values are printed in [S14 Table](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262#pmed.1005262.s024). **Funding:** This study was supported by Tri-Service General Hospital (grant TSGH-D-115176 to PHC; ) and by a collaborative research grant between Cheng Hsin General Hospital ( ) and National Defense Medical University ( ) (grant CHNDMU-115-02 to CHL). Role of the Funder/Sponsor: PHC, MSD, LTK, and CHL are affiliated with Tri-Service General Hospital and National Defense Medical University, and MHH is affiliated with Cheng Hsin General Hospital; these institutions are among those that funded this study. The funders had no other role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. **Competing interests:** The authors have declared that no competing interests exist. **Abbreviations:** BZD, benzodiazepine; CIs, confidence intervals; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; EHR, electronic health record; FDR, false discovery rate; GABA, against gamma-aminobutyric acid; GEP, Gene Expression Profile; HRs, hazard ratios; ICIs, Immune checkpoint inhibitors; irAE, immune-related adverse event; MAPK, mitogen-acti
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