In this study, Yang et al. report a CD5-targeted tri-specific NK cell engager (1H6-15-NKCE) as a potential immunotherapy for T cell malignancies. 1H6-15-NKCE enhances NK cell activation and cytotoxicity against malignant T cells, while avoiding on-target off-tumor lysis of normal autologous T cells.

Van Laethem et al. report that the combination of mFOLFIRINOX and mitazalimab has manageable safety and encouraging activity. Mitazalimab-induced immune activation and a fibrosis gene signature correlate with better outcomes. These results may inform future patient stratification strategies supporting a planned randomized confirmatory trial in mPDAC.

In this study, Weber et al. present ROR2 as a target for CAR T cell therapy of hematologic and solid tumors. ROR2 CAR T cells are effective against xenograft models of multiple myeloma and clear cell renal cell cancer in vitro and in vivo, without clinical signs of toxicity.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Fontana et al. demonstrate that multiplex base editing of the BCL11A +58-kb and +55-kb enhancers disrupts two key transcriptional activator motifs and leads to robust HbF induction with minimal generation of double-strand breaks and genomic rearrangements. This approach is safe, efficient, and durable in long-term repopulating hematopoietic stem cells.

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.

Medical AI is evolving from single-task tools to autonomous “agents” capable of complex reasoning and action. Liu et al. provide a unifying framework for these agents, exploring their transformative applications in clinical workflows while critically analyzing the profound technical, ethical, and regulatory challenges to their real-world implementation.

Xie et al. present that Eubacterium limosum, a gut symbiont, releases ursodeoxycholic acid to suppress renal IRI progression. This metabolite promotes PPARγ activity and increases fatty acid oxidation, inducing ATP production and reducing lipid accumulation in proximal tubular epithelial cells, ultimately protecting the kidney against IRI.

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.

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.

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.

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.

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.

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.

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.