Challenges and perspectives of CAR-T cell therapy in solid tumours: insights from gastric cancerZhou, Jincai
doi: 10.1038/s41416-025-03100-7pmid: 40615715
Gastric cancer (GC) remains a significant challenge as it is one of the most prevalent and lethal malignancies worldwide. Due to its complexity characterised by diverse histological subtypes and genetic mutations, its management and treatment remain a substantial challenge. Recent advancements in surgery, chemotherapy, and radiation therapy have only marginally improved the prognosis for advanced GC, underscoring the urgent need for innovative therapeutic strategies. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a breakthrough in haematologic malignancies and is now being investigated as a potential treatment for solid tumours. The remarkable efficacy of CAR-T in GC has been demonstrated in both preclinical and clinical studies. Potential biomarkers for GC treatment include CLDN18.2, MSLN, CEA, EpCAM, MUC1, HER2, FOLR1, and NKG2DL. However, applying CAR-T cells directed against GC still faces considerable challenges. Novel CAR designs have the potential to enhance CAR-T cell therapy for GC by facilitating T cell infiltration, enhancing T cell persistence, reducing on-target off-tumour toxicity, improving tolerance to the immunosuppressive tumour microenvironment (TME), and bolstering interactions with heterogeneous antigens. This review summarises relevant preclinical studies and clinical progress in CAR-T cell therapy for GC, evaluates its therapeutic potential and safety, discusses current challenges, and outlines future directions for clinical translation.
Impact of gut microbiome on radiotherapy and immunotherapy efficacy in microsatellite-stable colorectal cancer: role of propionic acid and B. fragilisYu, Lu; Guo, Qiqing; Gu, Xinyi; Wang, Zihuan; Li, Jiaying; Wang, Xusheng; Xu, Zi; Wang, Yafang; Zhang, Yuqin; Zhang, Yaowei; Ding, Yanqing; Chen, Zhenhui; Chen, Keli; Ding, Yi
doi: 10.1038/s41416-025-03105-2pmid: 40715695
BackgroundColorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. While immunotherapy is effective in microsatellite instability-high (MSI-H) CRC, its benefits in microsatellite-stable (MSS) CRC are limited. Radiotherapy may modify the immune microenvironment in MSS-CRC, enhancing immunotherapy efficacy, but individual responses vary.MethodsWe employed MSS-CRC mouse models to examine the effects of combined radiotherapy and immunotherapy, with and without antibiotics (ABX). Various analyses, including metagenomic, nontargeted metabolomic, and gas chromatography-mass spectrometry (GC-MS), were performed to identify factors influencing treatment outcomes. Flow cytometry, immunohistochemistry and in vivo antibody blockade experiments assessed the role of metabolites and bacteria on CD8+ T cell infiltration and treatment responses, complemented by transcriptomic sequencing and molecular biology experiments.ResultsOur analyses identified propionic acid and Bacteroides fragilis (B. fragilis) as crucial factors enhancing the efficacy of combined therapies in MSS-CRC. Both propionic acid and B. fragilis improved CD8+ T cell infiltration and treatment outcomes, with molecular assays indicating that propionic acid facilitates H3K14 acetylation, activating the Meox1-Cxcr6/Ccl5 axis.ConclusionsThis study highlights the pivotal role of the gut microbiome, specifically propionic acid and B. fragilis, in modulating the efficacy of combined radiotherapy and immunotherapy in MSS-CRC.[graphic not available: see fulltext]
A cancer-associated TP53 synonymous mutation induces synthesis of the p53 isoform p53/47Sajwan, Rhythm; Wang, Lixiao; Casar-Borota, Olivera; Karakostis, Konstantinos; Chen, Sa; Fahraeus, Robin; Gu, Xiaolian; Vadivel Gnanasundram, Sivakumar
doi: 10.1038/s41416-025-03127-wpmid: 40715694
BackgroundSynonymous mutations (SMs) change the mRNA nucleotide sequences without altering the corresponding amino acid sequence and are usually overlooked due to their perceived lack of influence on protein function. However, emerging reports suggest that SMs play a significant role in disease development and progression.MethodsWhole exome sequencing, RNA-sequencing, and droplet digital PCR were performed to identify the SMs from the malignant glioma patients. MutaRNA was used to predict the effect of SMs on RNA structure in silico. SHAPE-MaP was performed to probe and assess the effect of SMs on RNA structure in-cellulo.ResultsHere, we report that a Cancer-Associated SM in TP53 codon valine 203 (CASM203) results in the induction of the alternative translation initiated p53 protein isoform, p47. In-cell high-throughput RNA structural mapping showed that CASM203 mimics the Protein Kinase RNA-Like ER Kinase (PERK)-mediated p53 mRNA secondary structure that induces p47 expression of during the unfolded protein response (UPR).ConclusionsOverall, the single gain-of-function SM mimics the UPR-mediated p53 stress response, by generating RNA secondary structures akin to the PERK-mediated p53 mRNA structural switch. This illustrates the link between RNA structures and cellular biology and underscores the importance of SMs in cancer biology and their potential to further refine genetic diagnostics.
Enhanced HER2 internalization by clathrin-dependent endocytosis in non-small cell lung cancer positive for HER2 mutationsShimauchi, Atsushi; Iwama, Eiji; Ibusuki, Ritsu; Tsutsumi, Hirono; Shibahara, Daisuke; Otsubo, Kohei; Yoneshima, Yasuto; Tanaka, Kentaro; Okamoto, Isamu
doi: 10.1038/s41416-025-03126-xpmid: 40721523
BackgroundHER2-targeted antibody–drug conjugates (ADCs) have shown marked efficacy for HER2 mutation-positive non-small cell lung cancer (NSCLC). The intracellular trafficking of mutant HER2 has remained to be fully elucidated, however.MethodsHER2 dynamics were examined in cells expressing wild-type (WT) or mutant HER2 with the use of live cell imaging and an in situ proximity ligation assay. Proteins related to mutant HER2 trafficking were identified by liquid chromatography and tandem mass spectrometry.ResultsHER2 internalization was enhanced in NSCLC cells expressing mutant HER2 compared with those expressing HER2(WT). Homodimers of HER2(WT) were localized mainly at the cell surface, whereas those of mutant HER2 were present mostly in the cytoplasm. Knockdown of EGFR or HER3 suppressed internalization of HER2(WT) but not that of mutant HER2. The enhanced internalization of mutant HER2 was mediated by clathrin-dependent endocytosis, as was reflected by increased binding of the ubiquitin ligase c-Cbl to mutant HER2 and its consequent ubiquitination, and was attenuated by treatment with zongertinib, a HER2-specific tyrosine kinase inhibitor.ConclusionsUpregulation of HER2 phosphorylation promotes internalization of mutant HER2 mediated by clathrin-dependent endocytosis, likely contributing to the efficacy of HER2-targeted ADCs in NSCLC positive for HER2 mutations.[graphic not available: see fulltext]
Predictive efficacy and role of 2HG in MGMT promoter methylation in gliomas: a retrospective study based on MRS and mediator variable analysisGe, Ying; Yu, Meimei; Chang, Tianjing; Wang, Zixuan; Zhang, Yang; Chen, Hongyan; Chen, Xuzhu; Li, Xin; Ji, Nan; Shen, Huicong
doi: 10.1038/s41416-025-03132-zpmid: 40739045
BackgroundThe role of 2-hydroxyglutarate (2HG) in the methylation process of O6-methylguanine-DNA methyltransferase (MGMT) promoter remains unclear. This study aimed to investigate the predictive efficacy and role of 2HG in MGMT promoter methylation.MethodsPatients who met the inclusion criteria were retrospectively included and divided into MGMT promoter methylation group (M) and MGMT promoter unmethylation group (UM). 2HG, Glutamate (Glu), N-acetylaspartate (NAA), Choline (Cho), 2HG/Creatine (Cr), 2HG/Glu and Cho/NAA were calculated. Intergroup differences were estimated using Mann-Whitney U test and Chi-square test. Subsequently, the receiver operating characteristic (ROC) curves were plotted for evaluating diagnostic efficacy of metabolic indices with statistical differences. Then, the causal steps approach was performed for discussing the mediation effect of 2HG.Results75 patients (male: 52, female: 23, age: 46.81 ± 1.52 years) were included (48 in M, 27 in UM). Compared with UM, M exhibited higher 2HG, 2HG/Cr, 2HG/Glu, Cho/NAA and lower Glu, the differences were statistically significant (P < 0.05). 2HG/Glu exhibited the best diagnostic efficacy (area under curve: 0.788, [95%CI: 0.679–0.879]). 2HG is a mediator in the process of MGMT promoter methylation.Conclusions2HG/Glu exhibited the best efficacy in predicting MGMT promoter methylation, and 2HG is a mediator in the methylation process of MGMT promoter.
Randomised phase-2 screening trial of intermittent energy restriction plus resistance exercise versus resistance exercise alone during chemotherapy for advanced breast cancerHarvie, Michelle; Pegington, Mary; Howell, Anthony; Lim, Yit; Livingstone, Karen; Rose, Danielle; McMullan, Debbie; Maxwell, Anthony; Barrett, Emma; Sellers, Katharine; Krizak, Suzanne; Howell, Sacha J.
doi: 10.1038/s41416-025-03129-8pmid: 40745221
BackgroundWeight control and energy restriction could improve survival in patients with advanced breast cancer (ABC) but randomised data are lacking. A randomised screening trial was conducted to assess an intermittent energy restricted diet and resistance exercise intervention (IER + RE) vs RE alone (RE) on progression free survival (PFS), toxicity and Quality of Life (QoL) during chemotherapy for ABC.MethodsSixty-eight women were randomised to IER + RE (n = 35) or RE (n = 33) with one-sided significance assessed at the 20% threshold. The primary end point was PFS secondary endpoints included chemotherapy toxicity, weight change and QoL.ResultsThe adjusted hazard rate for progression comparing IER + RE vs RE was 0.729 (0.391–1.361) and the median PFS 42.0 vs 26.1 weeks respectively (p = 0.160). Toxicity was low and comparable between groups. Comparing IER + RE vs RE alone at cycle 3 the median (interquartile range) changes were: weight –1.8 kg (–4.2 to –0.7) vs +0.2 kg (–0.74, 2.59) (p < 0.001), FACT-B + 4.0 (–0.8, 11) vs +1.0 (–4.0, 4.0) (p = 0.031) and Hospital Anxiety Depression Score –2.0 (–3.5, +0.5) vs +1.0 (–2, 3.5) (p = 0.022).ConclusionIER + RE improved PFS and QoL without evidence of harms warranting a further larger randomised study in ABC.Trial registrationhttps://www.isrctn.com/ISRCTN12841416.