Spatial omics technology potentially promotes the progress of tumor immunotherapyLan, Zhen; Yang, Yuanyuan; Li, Lingling; Wang, Chaoguan; Sun, Zhenqiang; Wang, Qiming; Liu, Yang
doi: 10.1038/s41416-025-03075-5pmid: 40456924
Immunotherapy has become an indispensable modality in the treatment of cancer, yet challenges such as resistance and substantial variability in therapeutic responses among patients remain significant obstacles. Key technologies, including spatial omics, have emerged as critical methods for exploring the complex tumor microenvironment. Increasing evidence suggests that, compared to single-cell sequencing, spatial omics technologies offer the advantage of preserving spatial context and integrating multimodal analyses, thereby advancing our understanding of complex interactions within biological tissues. In this perspective article, we present a comprehensive overview of the origins, classifications, and characteristics of various modalities of spatial omics analyses. Furthermore, we discuss the heterogeneity of the TME in the spatial context, such as the phenotypic differences between B cells and T cells near normal versus tumorous tissues—where they predominantly express immune-suppressive receptors in proximity to the tumor. Additionally, we summarize the applications of spatial omics in different cancer therapies, recent advancements in exploring cellular interactions and tertiary lymphoid structures, and the challenges faced in clinical translation. In light of these findings, we advocate for a broader application of spatial omics, combined with other technologies, as this will unveil overlooked therapeutic targets and could potentially realize precision immunotherapy for cancer.
Deciphering the role of IGF2BP2 and PRMT5 in gallbladder cancer progression: insights from multi-omics analysisYang, Xinwei; Sun, Lingqi; Guo, Jiamin; Zheng, Yichen; Ren, Tonghui; Liu, Ying; Zheng, Lingnan; Ma, Ji
doi: 10.1038/s41416-025-03062-wpmid: 40555776
BackgroundGallbladder cancer (GBC) is a highly aggressive malignancy with limited therapeutic options and a poor prognosis. Elucidating the molecular mechanisms driving GBC progression is essential for identifying novel therapeutic targets.MethodsSingle-cell transcriptomics, high-throughput sequencing, and proteomics techniques were employed to investigate the role of the IGF2BP2-PRMT5 axis in GBC. Functional assays were conducted to assess cell proliferation, invasion, and migration, while mechanistic studies examined the impact of N6-methyladenosine (m6A) modifications and downstream signalling pathways. Furthermore, a humanised mouse model was utilised to examine the impact of this axis on immune cell infiltration and tumour immune evasion.ResultsIGF2BP2 was found to stabilise PRMT5 expression via m6A modifications, thereby promoting GBC cell proliferation, invasion, and migration. Mechanistically, PRMT5 activated the AKT/mTOR pathway, upregulated SREBP1, and reprogrammed lipid metabolism, leading to increased lipid synthesis and accumulation. Functional assays and in vivo experiments revealed that modulation of the IGF2BP2-PRMT5 axis significantly influenced immune cell infiltration, fostering immune evasion.ConclusionsThe IGF2BP2-PRMT5 axis is critical in GBC progression by orchestrating metabolic reprogramming and immune modulation. Targeting this axis holds potential as a therapeutic strategy for combating GBC.
Spliceosomal GTPase EFTUD2 mediates DDX41 intron retention to promote the malignant progression of ovarian cancerLiu, Yanling; Chen, Zhongshao; Duan, Yan; Shao, Zixian; Chen, Yuliang; Yang, Ning; Xiao, Huimin; Li, Yingwei; Song, Kun
doi: 10.1038/s41416-025-03079-1pmid: 40555777
BackgroundDysregulation of alternative splicing (AS) has been identified as a promising target for cancer therapy. Nevertheless, the precise molecular mechanisms by which AS influences ovarian cancer (OC) progression have not yet been fully elucidated.MethodsA comprehensive bioinformatics analysis was conducted to identify and screen core splicing factors in OC. The splicing factor EFTUD2 was found to be significantly overexpressed in clinical OC samples. Subsequent in vitro and in vivo assays elucidated the oncogenic role of EFTUD2 in OC. RNA-seq and AS events analysis were employed to determine the key downstream target regulated by EFTUD2. ASOs targeting EFTUD2 were developed for efficacy validation.ResultsEFTUD2 was identified as a critical splicing factor in the pathogenesis of OC, and EFTUD2 knockdown impeded OC tumorigenesis and progression. The EFTUD2-ASO significantly inhibited tumor growth in vivo. Mechanistically, EFTUD2 was shown to promote the malignant biological behavior of OC by facilitating the efficient splicing of DDX41 and maintaining the oncogenic expression of its functional proteins. Knockdown of DDX41 partially mitigated the EFTUD2-induced malignant progression of OC cells.ConclusionsOur findings suggest that the EFTUD2/DDX41 axis is a viable target for OC. ASO-mediated silencing of EFTUD2 presents promising new therapeutic options for OC patients.
GX-I7, a long-acting IL-7, safely and effectively increased peripheral CD8+/CD4+ T cells and TILs in patients with locally advanced or metastatic solid tumoursKim, Gun Min; Kim, Sojeong; Lee, Myung Ah; Byun, Mi-Sun; Choi, Donghoon; Yang, Se Hwan; Woo, JungWon; Sung, Young Chul; Shin, Eui-Cheol; Park, Su-Hyung; Kim, Tae Won; Sohn, Joohyuk
doi: 10.1038/s41416-025-03069-3pmid: 40490502
BackgroundGX-I7 (rhIL-7-hyFc, efineptakin alfa) is a hybrid Fc-fused long-acting interleukin-7 (IL-7) with the aim of correcting T-cell deficiency, thereby strengthening the immune response to fight against cancer. This Phase 1b, dose-escalation study was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GX-I7 in patients with locally advanced or metastatic solid tumours.MethodsThis study, conducted in patients with advanced solid tumours at three hospitals in Korea, involved intramuscular GX-I7 administration across eight dose levels (60–1700 µg/kg) in 3- and 6-week cohorts. A dose-expansion phase at 720 and 1200 µg/kg further assessed GX-I7’s safety and efficacy.ResultsAnti-tumour responses showed either stable disease (SD) or disease progression (PD). GX-I7 demonstrated dose-dependent increases in the maximum serum concentration (Cmax) and area under the curve up to the last measurable concentration (AUClast). In addition, a dose-dependent increase in circulating CD8+/CD4+ T cells was observed. In five patients who consented for biopsy, a statistically significant increase in tumour-infiltrating lymphocytes (TILs) followed GX-I7 treatment.DiscussionFindings suggest GX-I7 is a safe T cell-amplifying agent with peripheral immune activation. Ongoing studies are exploring its ability to enhance immune responses in peripheral immune cells and tumour cells when combined with other anti-cancer agents.Clinical Trial registrationNCT03478995
Growth kinetics of high-grade serous ovarian cancer: implications for early detectionNarayanan, Bharath; Buddenkotte, Thomas; Smith, Hayley; Shah, Mitul; Freeman, Susan; Hulse, David; Funingana, Gabriel; Alcaraz, Marie-Lyne; Crispin-Ortuzar, Mireia; Brenton, James; Pharoah, Paul; Pashayan, Nora
doi: 10.1038/s41416-025-03082-6pmid: 40506518
BackgroundHigh-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological cancer with patients routinely diagnosed at advanced stages. Evidence from randomized controlled trials indicates that annual screening may not reduce cancer-related deaths. We aim to characterise the growth kinetics of HGSOC to understand why early detection failed and under what conditions it might prove fruitful.MethodsWe analysed data from 597 HGSOC patients and identified 34 cases with serial CT scans. We calculated the growth rates of lesions in the ovaries/pelvis and the omentum and estimated the time to metastasis using a Gompertz model. Finally, we simulated ultrasound and CA125 based screening in a virtual population of patients.ResultsGrowing lesions in the ovaries and the omentum doubled in volume every 2.2 months and 1.8 months respectively. The 11 cases with growing lesions in both sites had a median interval of 13.1 months between disease initiation and the onset of metastasis. Our simulations suggested that 27% of tumours would metastasise before screen detection. The remainder would provide a median window of 4.2 months for detection before metastasis.ConclusionOur results suggest that HGSOC lesions have short times to metastasis, preventing effective early detection using current screening approaches.
Statin use and breast cancer-specific mortality and recurrence: a systematic review and meta-analysis including the role of immortal time bias and tumour characteristicsScott, Oliver William; Tin Tin, Sandar; Cavadino, Alana; Elwood, J. Mark
doi: 10.1038/s41416-025-03070-wpmid: 40500317
BackgroundThe association between statins and breast cancer-specific mortality and recurrence has been examined in several previous observational studies and meta-analyses. However, potentially important effect modifiers have not often been explored in previous meta-analyses. In this study, an updated systematic review and meta-analysis was undertaken to ascertain the association between statins and both breast cancer death (BCD) and breast cancer recurrence (BCR).MethodsArticles were sourced from various databases up until the 13th of June 2024, and effect estimates were pooled using the random effects model. Subgroup analyses were conducted by the potential for immortal time bias (ITB), type of statin (lipophilic vs hydrophilic), estrogen receptor status (positive vs negative), stage (‘early’ vs ‘advanced’), and type of postdiagnostic use (‘new’ vs ‘prevalent’ user).ResultsPooled results showed that there was a statistically significant protective association between statin use and both BCD (21 studies, hazard ratio = 0.81, 95% CI: 0.75–0.87) and BCR (20 studies, HR = 0.81, 95% CI: 0.74–0.89). Lipophilic statins were more protective than hydrophilic statins with BCD as the outcome, and there were suggestions of a more protective association in studies with ITB and in ER+ patients with BCR as the outcome. There was little evidence of effect modification by stage or type of postdiagnostic use.ConclusionIn this meta-analysis, we observed that statin use, particularly lipophilic statin use, was associated with favourable outcomes for BCD and BCR.