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Peer-reviewedCC BY 4.0PLOS Medicine

Selective serotonin reuptake inhibitors and immune checkpoint blockade in solid tumors: A target trial emulation with pan-cancer transcriptomic analyses

  • Po-Huang Chen1
  • Ming-Shen Dai2
  • Mao-Hsuan Huang3
  • Hsin-Yu Chen4
  • Li-Ting Kao5
  • Tina Yi-Jin Hsieh6
  • Hong-Jie Jhou7
  • Cho-Hao Lee8
8 affiliations
  1. 1Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan
  2. 2Department of Oncology, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan
  3. 3Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan
  4. 4Department of Family Medicine, Chi Mei Medical Center, Tainan, Taiwan
  5. 5Graduate Institute of Life Sciences, National Defense Medical University, Taipei, Taiwan
  6. 6School of Pharmacy, National Defense Medical University, Taipei, Taiwan
  7. 7Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan
  8. 8Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
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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 < 0.001; E-value 2.57). 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 by thyroid dysfunction (HR 1.199; 95% CI [1.053, 1.366]; p = 0.006), without increases in hepatitis, pneumonitis, or colitis (all p > 0.09). Newly coded distant metastases were less frequent in the SSRI group (HR 0.629; 95% CI [0.487, 0.811]; p < 0.001), and the 3 prespecified negative controls (nephrolithiasis, cholelithiasis, cataract) showed null associations (all 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. Why was this study done?: What did the researchers do and find?: What do these findings mean?: In this target trial emulation, Po-Huang Chen and colleagues compare outcomes between selective serotonin reuptake inhibitor and benzodiazepine users with solid tumors and depression or anxiety and find that patients receiving immune checkpoint inhibitors who initiated selective serotonin reuptake inhibitors had lower mortality than those initiating benzodiazepines.

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Cite

BibTeXRIS
BibTeX
@article{chen2026selective,
  title = {{Selective serotonin reuptake inhibitors and immune checkpoint blockade in solid tumors: A target trial emulation with pan-cancer transcriptomic analyses}},
  author = {Po-Huang Chen and Ming-Shen Dai and Mao-Hsuan Huang and Hsin-Yu Chen and Li-Ting Kao and Tina Yi-Jin Hsieh and Hong-Jie Jhou and Cho-Hao Lee},
  journal = {PLOS Medicine},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pmed.1005262},
  url = {https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Selective serotonin reuptake inhibitors and immune checkpoint blockade in solid tumors: A target trial emulation with pan-cancer transcriptomic analyses
AU  - Po-Huang Chen
AU  - Ming-Shen Dai
AU  - Mao-Hsuan Huang
AU  - Hsin-Yu Chen
AU  - Li-Ting Kao
AU  - Tina Yi-Jin Hsieh
AU  - Hong-Jie Jhou
AU  - Cho-Hao Lee
PY  - 2026
DA  - 2026/09/29
JO  - PLOS Medicine
DO  - 10.1371/journal.pmed.1005262
UR  - https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1005262
AB  - 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 < 0.001; E-value 2.57). 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 by thyroid dysfunction (HR 1.199; 95% CI [1.053, 1.366]; p = 0.006), without increases in hepatitis, pneumonitis, or colitis (all p > 0.09). Newly coded distant metastases were less frequent in the SSRI group (HR 0.629; 95% CI [0.487, 0.811]; p < 0.001), and the 3 prespecified negative controls (nephrolithiasis, cholelithiasis, cataract) showed null associations (all 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. Why was this study done?: What did the researchers do and find?: What do these findings mean?: In this target trial emulation, Po-Huang Chen and colleagues compare outcomes between selective serotonin reuptake inhibitor and benzodiazepine users with solid tumors and depression or anxiety and find that patients receiving immune checkpoint inhibitors who initiated selective serotonin reuptake inhibitors had lower mortality than those initiating benzodiazepines.
SN  - 1549-1676
ER  -