--- title: "Sertraline plus Carfilzomib Synergy Targets SSP-Active T-cell Malignancies via Cholesterol Dysregu" id: "biorxiv-3-sertraline-and-carfilzomib-synergize-to-target-t-cell-malignancies-with-serine" canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-3-sertraline-and-carfilzomib-synergize-to-target-t-cell-malignancies-with-serine" content_type: "clinical_feed_article" specialty: "Oncology" source_name: "bioRxiv (Biomedical Preprints)" source_url: "https://www.biorxiv.org/content/10.64898/2026.08.17.744660v1?rss=1" published_at: "2026-08-17T12:00:00.000Z" evidence_level: "Verified Feed" license: "CC-BY-NC-4.0 / Informational Use" --- # Sertraline plus Carfilzomib Synergy Targets SSP-Active T-cell Malignancies via Cholesterol Dysregu ## Provenance & Clinical Metadata - **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-3-sertraline-and-carfilzomib-synergize-to-target-t-cell-malignancies-with-serine - **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md) - **Primary Source:** bioRxiv (Biomedical Preprints) - **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.17.744660v1?rss=1) - **Published At:** 2026-08-17T12:00:00.000Z - **Evidence Rating:** Verified Feed ## Executive GIST (TL;DR) - T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphoma (PTCL) are aggressive hematologic cancers that frequently rely on endogenous **serine/glycine synthesis (SSP)** for metabolic activity and survival. - The antidepressant **sertraline** inhibits SSP enzymes SHMT1/2 and can induce cell cycle arrest in SSP-active T-cell malignancies, but as monotherapy it shows limited in vivo disease suppression. - The proteasome inhibitors **carfilzomib** and bortezomib were tested for synergy with sertraline; carfilzomib showed strong synergistic activity with sertraline in SSP-active T-ALL and PTCL cells. - The sertraline–carfilzomib combination induced cell cycle arrest and apoptosis in SSP-active tumor cells while sparing SSP-inactive T-ALL cells and healthy blood cells. - Mechanistically, sertraline rewired tumor cell metabolism toward increased **cholesterol** uptake and biosynthesis; carfilzomib promoted cholesterol efflux and reduced total lipid levels, further restricting lipid resources. - The drug pair impaired mitochondrial respiration, increased reactive oxygen species (ROS) and DNA damage in SSP-active cells; these effects were rescued by citrate supplementation, linking metabolic substrate availability to cytotoxicity. - Proteomic, lipidomic and metabolic profiling supported these findings and shRNA knockdown of SSP enzymes validated target relevance. - In an immunocompetent MYCN-driven PTCL mouse model, addition of carfilzomib enhanced sertraline’s therapeutic efficacy and the combination altered the tumor microenvironment, increasing natural killer T cells, neutrophils and eosinophils. - The study proposes that combined metabolic impairment and immune microenvironment remodelling mediate the therapeutic synergy and supports further clinical investigation of sertraline–carfilzomib for SSP-active T-cell malignancies. ## Clinical Analysis & Structured Key Points Background: T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphoma (PTCL) are aggressive hematological malignancies requiring novel therapeutic strategies. The majority of T-ALL and PTCL tumors display metabolic activation and addiction to endogenous serine/glycine synthesis (SSP), providing opportunities for targeted therapy with the clinically used antidepressant sertraline, inhibiting SSP enzymes SHMT1/2. However, sertraline monotherapy only induces cell cycle arrest and has limited efficacy to suppress disease progression in vivo. Methods: Drug synergy of sertraline combined with clinically used proteasome inhibitors carfilzomib and bortezomib was evaluated. Drug effects on cell cycle, proliferation and apoptosis were assessed in T-ALL, PTCL and healthy blood cells using flow cytometry assays. Proteomic, lipidomic and metabolic analyses on drug treated T-ALL cells were performed to elucidate the molecular mechanisms underlying drug synergy, followed by validation of changes of interest, metabolic rescues and shRNA-knockdown of SSP enzymes in T-ALL cells. In vivo therapeutic efficacy and immune remodelling were evaluated in an immunocompetent MYCN-overexpressing PTCL mouse model. Results: Sertraline acted synergistically with clinically used proteasome inhibitor carfilzomib to induce cell cycle arrest and apoptosis in T-ALL and PTCL cells with SSP activity, with minimal effects on SSP-inactive T-ALL cells or healthy blood cells. Adding carfilzomib also enhanced the therapeutic efficacy of sertraline in an aggressive MYCN PTCL model. Sertraline rewired cell metabolism towards increased cholesterol uptake and biosynthesis in SSP-active T-ALL cells, and this effect was not obtained by other means of SSP inhibition. In contrast to sertraline, carfilzomib promoted cholesterol efflux. Moreover, carfilzomib reduced total lipid levels, further restricting nutrients in sertraline-carfilzomib treated cells. Additionally, the drug combination impaired mitochondrial respiration and elevated reactive oxygen species (ROS) levels and DNA damage in SSP-active tumor cells, which was rescued by citrate supplementation. Interestingly, these metabolic changes were associated with microenvironmental changes in our mouse model, where the drug combination elevated natural killer T-cells, neutrophils and eosinophils. Conclusions: Our study identifies synergy of sertraline-carfilzomib combination treatment mediated through metabolic impairment and is associated with remodelling of the immune microenvironment. 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