Cancer of unknown primary: the hunt for its elusive tissue-of-origin – is it time to call off the search?Spurgeon, Laura; Mitchell, Claire; Cook, Natalie; Conway, Alicia-Marie
doi: 10.1038/s41416-025-03073-7pmid: 40615718
Cancer of Unknown Primary (CUP) is an heterogenous group of metastatic cancers, for which the primary site cannot be identified despite thorough diagnostic work-up. Whilst it is a relatively rare entity, its aggressive nature, together with the paucity of effective treatments, mean it has a disproportionately high mortality rate. Advances in genomic profiling have driven research in the area, but despite this, therapeutic options and prognosis remain poor. For many years, the primary focus in CUP has been improving identification of the tissue-of-origin (TOO), with the hope that site-specific therapy will improve survival outcomes. However, the lack of conclusive evidence to support this, as well as an emerging paradigm shift in how cancers should be classified, has reignited the debate surrounding the importance of TOO. Here, we provide a comprehensive review of the ongoing relevance of TOO, within both the CUP and wider oncology landscape.
TIGIT antibody with PVR competitive ability enhances cancer immunotherapy and capable of eliciting anti-tumour immune memoryYu, Huijuan; Jin, Shaowen; Zeng, Min; Yang, Zhiqing; Wang, Xiaofei
doi: 10.1038/s41416-025-03046-wpmid: 40394151
BackgroundT-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) is a checkpoint receptor thought to be involved in mediating T-cell exhaustion and dysfunction of natural killer (NK) cells in tumours and is emerging as novel promising targets in immunotherapy, however, the ligand binding and the efficacy of its antibody still need to be further explored.MethodsFour different TIGIT antibodies in characteristics of antigen binding, in vitro effects on activated T cells, Fc region functions and tumour inhibition in animal models were compared. The antibody as monotherapy and combined with anti-PD-L1 antibody, effects on PBMC in ex vivo coculture with autologous human CRC organoids as well as PK profile were evaluated.ResultsStudies demonstrated that TIGIT antibody with PVR-competitive ability as monotherapy resulted in inhibition of tumour growth, sustained anti-tumour immune memory in tumour re-challenge mice, enhanced anti-tumour therapy in combination with anti-PD-L1. Ex vivo coculture assay suggested that TIGIT antibody treatment activated immune cells and promoted infiltration and tumour killing ability of autologous PBMC in human CRC organoids.ConclusionsOur study broadens the knowledge of TIGIT antibody in cancer immunotherapy and may benefit future development of next-generation checkpoint inhibitors with improved clinical outcomes.[graphic not available: see fulltext]
Targeting ribosomes reprograms the tumour microenvironment and augments cancer immunotherapyCui, Kaisa; Liu, Bingxin; Gong, Liang; Wan, Quan; Tang, Hong; Gong, Zhicheng; Shen, Renhui; Wang, Chao; Zhang, Qiang; Li, Qilin; Zhu, Yizhun; Zhang, Youming; Lu, Xiaojie
doi: 10.1038/s41416-025-03109-ypmid: 40646287
BackgroundHyperactive ribosome biogenesis is a hallmark of tumours. Current ribosome-related studies are concentrated on cancer cells. Ribosomes can regulate both tumour and non-cancer cells within the tumour microenvironment, yet the immunomodulatory effects of cellular ribosome biogenesis blockade remain inadequately understood.MethodsWe performed ribosome-targeting therapy utilizing CX-5461, an effective and acknowledged selective inhibitor of ribosome biogenesis, in immunocompetent in vivo models and submitted for single-cell RNA sequencing (scRNA-seq). Additional large-scale human scRNA-seq data, in-house clinical samples and assays were used.ResultsRibosome inhibition elevated lymphoid cell cytotoxic granule secretion and macrophage pro-inflammation reprogramming. We uncovered unique immune cell subpopulations that are sensitive to ribosome biogenesis blockade and are associated with adverse clinical outcomes. Impressively, these cells regress during responsive immune checkpoint blockade (ICB) treatment, revealing that they are essential for immunotherapy efficacy. Moreover, targeting ribosomes induces immune checkpoint expression (such as Lag3) and significantly sensitizes tumours to anti-Lag3 immunotherapy, eliciting potent tumour regression and deeper anti-tumour immune responses.ConclusionsThese findings unravel previously unrecognized roles of cellular ribosome biogenesis in sustaining immunosuppressive non-cancer cells. Our work unveils that ribosome biogenesis blockade could reinstate immunosurveillance and provide novel strategies to enhance the ICB efficacy in patients with poor immunogenicity.
Novel mutations of SRPX facilitate the stemness and malignant progression of gliomaTang, Siyuan; Qu, Chunhui; Zhang, Mingyu; Zhou, Peijun; Peng, Xingzhi; Zhou, Zhuan; Shen, Liangfang; Yang, Lifang
doi: 10.1038/s41416-025-03091-5pmid: 40665012
BackgroundExplorations of genomic profiles are of great clinical significance for glioma due to the high tumor heterogeneity and stemness. High-depth sequencing enabled to identify driver genes and potential treatment targets in glioma.MethodsA whole exome sequencing analysis of 27 Chinese patients was conducted and somatic mutation signatures were analyzed using validated computational methods. The biological roles of SRPX mutations and subsequent regulatory mechanisms were revealed by common experimental methods.ResultsWe intriguingly found that SRPX drove glioma progression with two frequent in-frame deletion mutations of p.L14DEL and p.L23DEL. Mechanistically, both the two mutations of SRPX promoted binding with transcription factor AHR on its promoter, upregulated gene transcription of itself, then activated EGFR/ Akt/ Nestin pathway and contributed to aggressive tumor phenotypes and animal tumor growth. Further, knockdown of AHR or application of Akt inhibitor suppressed the oncogenic role of mutated SRPX.ConclusionsOur study highlighted the landscape of glioma in revealing a non-distinctive mutation and signaling pathway profile between low and high grades. More importantly, we identified a novel role of SRPX mutations in acceleration to stemness and malignant progression, which could provide new targets in improving outcomes of glioma.
Fatigue in long-term cancer survivors: prevalence, associated factors, and mortality. A prospective population-based studyThong, Melissa S. Y.; Doege, Daniela; Koch-Gallenkamp, Lena; Bertram, Heike; Eberle, Andrea; Holleczek, Bernd; Nennecke, Alice; Waldmann, Annika; Zeissig, Sylke Ruth; Pritzkuleit, Ron; Brähler, Elmar; Brenner, Hermann; Arndt, Volker
doi: 10.1038/s41416-025-03116-zpmid: 40665014
BackgroundWe compared fatigue severity in breast, prostate or colorectal cancer survivors 5–16 years post-diagnosis with cancer-free controls, and examined factors associated with fatigue and its association with all-cause mortality in survivors.MethodsParticipants of the CAncEr Survivorship - A multi-Regional (CAESAR) study completed the Fatigue Assessment Questionnaire (FAQ) between 2009 and 2011. The FAQ assesses affective, cognitive, and physical fatigue, and sleep problems. We derived the odds of fatigue using logistic regression with the 75th percentile of population norms as the cut-off. All-cause mortality (up to end 2021) was estimated using Cox regression models.ResultsThe sample comprised 6057 survivors, of whom approximately one-third reported affective, cognitive, or physical fatigue. Demographic (age, relationship), clinical (chemotherapy), comorbidity (depression), lifestyle, and psychological factors were associated with higher odds of fatigue symptoms and total fatigue. Fatigue symptoms, predominantly physical fatigue, were strongly associated with mortality (unadjusted hazard ratios (HRs) ranged from 1.48 to 2.40). The HRs were attenuated after adjustment for comorbidities and depressive symptoms, although affective and physical fatigue remained independent risk factors for mortality.ConclusionsDemographic, clinical, comorbidity, lifestyle, and psychological factors were associated with fatigue in long-term survivors. Fatigued survivors have a higher mortality risk. Lowering the burden of fatigue by a comprehensive approach might result in better survival.