Cell Reports Medicine

Sintilimab plus chemotherapy for first-line treatment of advanced pulmonary lymphoepithelioma-like carcinoma: Phase 2 trial Lin et al. reveal that a prospective trial evaluating treatment for pulmonary lymphoepithelioma-like carcinoma (PLELC), a rare form of Epstein-Barr virus-associated lung cancer without standard therapies. Combining immunotherapy with chemotherapy proves effective in these patients, offering a needed potential treatment for this challenging cancer.

Online now: Sintilimab plus chemotherapy for first-line treatment of advanced pulmonary lymphoepithelioma-like carcinoma: Phase 2 trial

4-1BB+ Tregs and inhibitory progenitor exhausted T cells confer resistance to anti-PD-L1 and anti-CTLA-4 combination therapy Cha et al. show existence of immunotherapy-resistant progenitor exhausted T cells, demonstrating a key cellular factor determining successful cancer immunotherapy. Conflicting mechanisms both suppressing and promoting tumor are associated with anti-CTLA-4 and explain their varied clinical results.

Online now: 4-1BB+ Tregs and inhibitory progenitor exhausted T cells confer resistance to anti-PD-L1 and anti-CTLA-4 combination therapy

In situ extended immune activation instantly after tumor resection by oncolytic virus controls postoperative tumor recurrence Guo et al. report that a supramolecular hydrogel enables sustained oncolytic virus (OV) release. Administering this OV-loaded hydrogel instantly after tumor resection induces prolonged immune activation, effectively curbing postoperative tumor recurrence and metastasis and increasing survival in mice. This strategy represents a universal and clinically translatable approach for cancer immunotherapy.

Online now: In situ extended immune activation instantly after tumor resection by oncolytic virus controls postoperative tumor recurrence

Comprehensive dissection of rectal cancer organoids in responses to chemoradiation Xu et al. establish a rectal cancer organoid biobank and demonstrate its high accuracy in predicting clinical response, highlight time-dependent predictive accuracy of organoid assays, uncover synergistic or antagonistic effects of combined chemoradiation, and identify irinotecan as a promising neoadjuvant agent, providing valuable insights for organoid-guided precision oncology.

Online now: Comprehensive dissection of rectal cancer organoids in responses to chemoradiation

Updated efficacy and predictive biomarkers of QL1706, a bifunctional PD-1/CTLA-4 dual blocker in advanced solid tumors—A phase 1/1b study Ma et al. report sustained survival benefits with QL1706, a bifunctional PD-1/CTLA-4 dual blocker, in patients with advanced solid tumors. They further identify clinical risk factors associated with unfavorable prognosis and predictive biomarkers to stratify patients with nasopharyngeal carcinoma or non-small-cell lung cancer who are likely to benefit from immunotherapy.

Online now: Updated efficacy and predictive biomarkers of QL1706, a bifunctional PD-1/CTLA-4 dual blocker in advanced solid tumors—A phase 1/1b study

A sequential dual-site repetitive transcranial magnetic stimulation for major depressive disorder: A randomized clinical trial Zhao et al. developed an accelerated dual-site rTMS protocol sequentially targeting the left dlPFC and dmPFC, demonstrating rapid and sustained antidepressant effects, possibly through normalizing functional connectivity in depression-related neural networks of the two targets. This cost-efficient intervention requires fewer pulses, no neuronavigation, and enables convenient patient engagement over 4 half-days.

Online now: A sequential dual-site repetitive transcranial magnetic stimulation for major depressive disorder: A randomized clinical trial

Single-cell profiles delineate immune cell remodeling and enhanced tumor-fibroblast interaction of hepatoblastoma after chemotherapy Chen et al. study pre- and post-chemotherapy hepatoblastoma through scRNA-seq and spatial transcriptomics and discover an activated immune TME with activated cell-cell interactions. They identify enrichment of proliferative hepatic-like cells (HECs) related to chemo-resistance, which interact with CAFs through FGF-FGFR4 pathway, and thus provide insights into FGFR4 targeted therapeutic strategy.

Online now: Single-cell profiles delineate immune cell remodeling and enhanced tumor-fibroblast interaction of hepatoblastoma after chemotherapy

Designer probiotic-based living drugs for uric acid homeostasis control in hyperuricemic mice and rats Gao et al. develop a probiotic-based uric acid level sensing and adjustment system (PULSE) by equipping E. coli Nissle 1917 with a HucR-mediated uric acid-responsive genetic circuit. Oral administration of PULSE dynamically regulates urate oxidase expression, lowering serum uric acid levels and mitigating renal damage in hyperuricemic animal models.

Online now: Designer probiotic-based living drugs for uric acid homeostasis control in hyperuricemic mice and rats

Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density Quan et al. demonstrate that T cells engineered with antibody-T cell receptors (AbTCRs) targeting GPC2 outperform CAR T cells in neuroblastoma, showing improved efficacy due to stronger TCR signaling, greater memory T cell expansion, and increased CD8+ T cell infiltration, offering promising potential for neuroblastoma therapy.

Online now: Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density

Online now: Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease

Chromosomal instability degrades developmental phenotypes essential for anti-GD2 immunotherapy outcomes in high-risk neuroblastoma Rebernick et al. profile 840 tumors and identify actionable ALK gene fusions in high-risk neuroblastoma. Using fetal single-cell RNA sequencing, they demonstrate that developmental phenotypes are associated with outcomes following regimens containing anti-GD2 immunotherapy and that these phenotypes are degraded by chromosomal instability. Tumors progressing after treatment accumulated pro-proliferative cell-cycle mutations.

Online now: Chromosomal instability degrades developmental phenotypes essential for anti-GD2 immunotherapy outcomes in high-risk neuroblastoma

Online now: A foundational architecture for AI agents in healthcare

Online now: Gut symbiont-derived ursodeoxycholic acid promotes fatty acid oxidation to protect against renal ischemia-reperfusion injury

Phenotyping obesity through a two-dimensional tree structure reveals cardiometabolic heterogeneity Jia et al. visualize obesity heterogeneity in 18,733 individuals from the 4C study using 10 clinical variables. They identify and validate five distinct metabolic phenotypes, with varying risks of developing T2DM, CKD, and CVD, and provide an interactive data visualization tool for personalized risk prediction.

Online now: Phenotyping obesity through a two-dimensional tree structure reveals cardiometabolic heterogeneity

Vorapaxar enhanced mitochondria-associated ferroptosis primes cancer immunotherapy via targeting FOXO1/HMOX1 axis Zhou et al. identify vorapaxar, an FDA-approved antiplatelet agent, as an enhancer of ferroptosis and ferroptosis-mediated immunotherapy. Mechanistically, vorapaxar directly binds FOXO1, inhibits Ser256 phosphorylation to promote nuclear translocation, and transcriptionally upregulates HMOX1, thereby promoting mitochondrial iron overload and mitochondria-associated ferroptosis.

Online now: Vorapaxar enhanced mitochondria-associated ferroptosis primes cancer immunotherapy via targeting FOXO1/HMOX1 axis

Phocaeicola vulgatus induces immunotherapy resistance in hepatocellular carcinoma via reducing indoleacetic acid production Zhao et al. demonstrate that P. vulgatus is enriched in HCC non-responders and reduces anti-PD-1 efficacy by depleting IAA and suppressing CD8+ T cell function. IAA supplementation restores CD8+ T cell activity and counters microbial immunosuppression, with P. vulgatus and IAA serving as potential biomarkers for immunotherapy resistance and prognosis.

Online now: Phocaeicola vulgatus induces immunotherapy resistance in hepatocellular carcinoma via reducing indoleacetic acid production

Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques Styles et al. report that a chimeric influenza virus hemagglutinin-based mRNA-LNP vaccine induces a strong influenza virus stalk-specific antibody in serum and bone marrow plasma cells and define a transcriptional profile associated with induction of these responses in non-human primates.

Online now: Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques

The multiomics blueprint of the individual with the most extreme lifespan In brief, Santos-Pujol and colleagues characterize the multiomics landscape of the human with the most extreme longevity. The study enables the association of advantageous genetic variants, an engaged lipid metabolism, low inflammation levels, a proficient immune system, a rejuvenated microbiome composition, and a younger epigenetic age with the extraordinary lifespan.

Online now: The multiomics blueprint of the individual with the most extreme lifespan

Large language model as clinical decision support system augments medication safety in 16 clinical specialties Ong et al. explored how large language models (LLMs) support safe prescribing by detecting drug-related problems across clinical scenarios. The study demonstrated that LLMs augmented performance of pharmacists and improved overall accuracy of medication chart review. However, limitations in clinical generalizability, bias, and prompt design must be addressed before routine use.

Online now: Large language model as clinical decision support system augments medication safety in 16 clinical specialties

Translating the science of care and cure for children with cancer The past 50 years have seen great progress for children with cancer, and yet, this progress has been largely unreached for most children. We examine how global efforts aimed at spreading, scaling, and sustaining interventions to improve access, quality, and integration in systems and policies can transform the landscape.

Online now: Translating the science of care and cure for children with cancer

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Check out the science we have planned @CellSymposia #CSStemCells2025 from sessions on Cell replacement therapy; Emerging immune approaches; Aging & rejuvenation; Gene therapy; and Therapeutic screening. View the program and register: http://dlvr.it/TNJjYp

Phenotypic heterogeneity of type 2 diabetes and risks of all-cause and cause-specific mortality Qiu et al. visualize diabetes phenotypic variation in 10,091 adults with newly diagnosed T2D from a nationally representative Chinese cohort using a data-driven algorithm applied to seven clinical variables. They identify distinct phenotypes with differing mortality patterns, validate these findings, and develop an online tool for individualized risk prediction.

Online now: Phenotypic heterogeneity of type 2 diabetes and risks of all-cause and cause-specific mortality

FLT3L-based drug conjugate effectively targets chemoresistant leukemia stem cells in acute myeloid leukemia Zhang et al. develop FL-Fc-DM1, a FLT3L-based cytotoxic conjugate that targets cytarabine-resistant AML blasts and LSCs by promoting cell cycle re-entry and apoptosis. It reduces LSC frequency, shows synergy with BH3 mimetics, and spares normal hematopoiesis in humanized mice, making it a promising therapeutic for FLT3-mutated and wild-type AML.

Online now: FLT3L-based drug conjugate effectively targets chemoresistant leukemia stem cells in acute myeloid leukemia

A phase 1 trial of APG-1387, an IAP antagonist, with nab-paclitaxel and gemcitabine in patients with refractory metastatic pancreatic cancer Advanced pancreatic cancer lacks effective, well-tolerated options beyond chemotherapy. Shi et al. demonstrate that IAP antagonist APG-1387 combined with nab-paclitaxel and gemcitabine (AG) exhibits manageable safety without potentiating AG toxicity and demonstrates encouraging antitumor activity in AG-naive/resistant patients. APG-1387 monotherapy shows potential to maintain disease control in AG-intolerant cases.

Online now: A phase 1 trial of APG-1387, an IAP antagonist, with nab-paclitaxel and gemcitabine in patients with refractory metastatic pancreatic cancer

Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts Nishida-Aoki, Zhu, and Chan et al. performed drug screening on 3D microtumors to identify compounds that target the tumor microenvironment. Doramapimod inhibits cancer-associated fibroblasts via the DDR1/2-MAPK12-GLI axis, enhancing chemo- and immunotherapy. This study underscores the utility of 3D tumor models in discovering microenvironment-specific therapies.

Online now: Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts

🎉 New Special Issue on cardiometabolism! 🎉 Recent advances in #atherosclerosis therapies, #inflammaging, and more, with a stunning cover from Joseph Wu lab. Don't miss expert insights on gender disparities by Dr. Susan Cheng and GLP-1R therapeutics from Dr Gregory Steinberg. #cardiology

Cetuximab increases LGR5 expression and augments LGR5-targeting antibody-drug conjugate efficacy in patient-derived colorectal cancer models High et al. report that EGFR-targeting therapies such as cetuximab can increase LGR5 expression and promote EGFR-LGR5 interactions in colorectal cancer (CRC) cells. Importantly, cetuximab significantly enhances the efficacy of an LGR5-targeting antibody-drug conjugate in RAS wild-type and RAS mutant models, suggesting an improved strategy for the treatment for CRC.

Online now: Cetuximab increases LGR5 expression and augments LGR5-targeting antibody-drug conjugate efficacy in patient-derived colorectal cancer models

Therapeutic T cells with 3-in-1 strategy for the treatment of biliary tract cancer Wan et al. develop a 3-in-1 strategy for T cell therapy that demonstrates effective treatment outcomes for advanced biliary tract cancer (BTC). In a selected patient cohort, this approach achieved a median overall survival (OS) of 18.3 months, outperforming available standard therapy.

Online now: Therapeutic T cells with 3-in-1 strategy for the treatment of biliary tract cancer

Global, regional, and national burden of headache disorders, 1990–2021, with forecasts to 2050: A Global Burden of Disease study 2021 Using GBD 2021, Wijeratne et al. present updated global estimates and 2050 forecasts for migraine and tension-type headaches. Despite stable age-standardized rates, the burden remains high, especially among women aged 30–44 years, underscoring the need to prioritize headache disorders in global health policy and resource allocation.

Online now: Global, regional, and national burden of headache disorders, 1990–2021, with forecasts to 2050: A Global Burden of Disease study 2021

Lentiviral vectors for hematopoietic stem cell gene therapy restore α-globin expression in α-thalassemia red blood cells Segura et al. show that vectors encoding HBA2 under β-globin regulatory elements restore α-globin expression in red blood cells derived from hematopoietic stem and progenitor cells of alpha thalassemia major (ATM) patients. Correction of the α/β-globin ratio enables hemoglobin production, supporting gene addition as a promising therapy for ATM.

Online now: Lentiviral vectors for hematopoietic stem cell gene therapy restore α-globin expression in α-thalassemia red blood cells