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

backgroundPreclinical 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

findingsWe 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.

conclusionsIn 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.