Pub Date : 2025-12-16DOI: 10.1016/j.critrevonc.2025.105092
Fabio Salomone , Massimo Di Maio , Angela Viggiano , Luigi Liguori , Carminia Maria Della Corte , Giuseppe Viscardi , Fabiana Vitiello , Fabiana Napolitano , Antonio Santaniello , Antonio Nuccio , Simeone D’Ambrosio , Filippo Vitale , Annarita Avanzo , Alessandra Bulotta , Luigi Formisano , Roberto Ferrara , Roberto Bianco , Valter Torri , Alberto Servetto
Background
The ability of progression-free survival (PFS) and overall response rate (ORR) to predict overall survival (OS) outcomes in cancer trials is matter of debate. Herein, we investigated whether PFS and ORR predicted OS results in randomized clinical trials (RCTs) testing immune checkpoint inhibitors (ICIs) in advanced NSCLC.
Methods
ORR (ORORR,%ORR), OS (HROS,mOS) and PFS (HRPFS,mPFS) data were collected from phase III RCTs investigating ICIs in advanced NSCLC. Linear regression, weighted by sample size, between surrogate endpoints and OS were calculated. The power of correlation was defined by the value of coefficient of determination R2 (≥0.7 strong, 0.69–0.50 moderate, <0.5 weak).
Results
Forty investigational arms of ICIs ± chemotherapy (ChT) were identified for further investigation. Arm-level analysis revealed that mPFS had a strong correlation with mOS in all comparisons (R2=0.71), in ICIs+ChT trials (R2=0.81) and in first-line setting (R2=0.71). A weak correlation was found between mPFS-mOS (R2=0.48) in trials of ICIs without chemotherapy. Next, trial-level analysis revealed a weak correlation between HROS and HRPFS in all different groups, except in ICIs+ChT trial (R2=0.60). In addition, based on arm-level analysis, mOS and %ORR had moderate correlation in all comparisons (R2=0.58), in ICIs+ChT (R2=0.58) or ICIs (R2=0.53). In trial-level analysis, ORORR and HROS had moderate correlation (R2=0.55) in first-line setting and a strong correlation in ICIs+ChT trials (R2=0.79).
Conclusions
Across trials investigating ICIs in advanced NSCLC, PFS and ORR demonstrated various degrees of relationship with OS. Caution should be taken when efficacy of novel ICIs regimens is evaluated only using surrogate outcomes.
{"title":"Correlation of ORR and PFS with OS outcomes in phase III trials of immunotherapy in advanced NSCLC: Systematic review and meta-analysis","authors":"Fabio Salomone , Massimo Di Maio , Angela Viggiano , Luigi Liguori , Carminia Maria Della Corte , Giuseppe Viscardi , Fabiana Vitiello , Fabiana Napolitano , Antonio Santaniello , Antonio Nuccio , Simeone D’Ambrosio , Filippo Vitale , Annarita Avanzo , Alessandra Bulotta , Luigi Formisano , Roberto Ferrara , Roberto Bianco , Valter Torri , Alberto Servetto","doi":"10.1016/j.critrevonc.2025.105092","DOIUrl":"10.1016/j.critrevonc.2025.105092","url":null,"abstract":"<div><h3>Background</h3><div>The ability of progression-free survival (PFS) and overall response rate (ORR) to predict overall survival (OS) outcomes in cancer trials is matter of debate. Herein, we investigated whether PFS and ORR predicted OS results in randomized clinical trials (RCTs) testing immune checkpoint inhibitors (ICIs) in advanced NSCLC.</div></div><div><h3>Methods</h3><div>ORR (OR<sub>ORR</sub>,%ORR), OS (HR<sub>OS</sub>,mOS) and PFS (HR<sub>PFS</sub>,mPFS) data were collected from phase III RCTs investigating ICIs in advanced NSCLC. Linear regression, weighted by sample size, between surrogate endpoints and OS were calculated. The power of correlation was defined by the value of coefficient of determination R<sup>2</sup> (≥0.7 strong, 0.69–0.50 moderate, <0.5 weak).</div></div><div><h3>Results</h3><div>Forty investigational arms of ICIs ± chemotherapy (ChT) were identified for further investigation. Arm-level analysis revealed that mPFS had a strong correlation with mOS in all comparisons (R<sup>2</sup>=0.71), in ICIs+ChT trials (R<sup>2</sup>=0.81) and in first-line setting (R<sup>2</sup>=0.71). A weak correlation was found between mPFS-mOS (R<sup>2</sup>=0.48) in trials of ICIs without chemotherapy. Next, trial-level analysis revealed a weak correlation between HR<sub>OS</sub> and HR<sub>PFS</sub> in all different groups, except in ICIs+ChT trial (R<sup>2</sup>=0.60). In addition, based on arm-level analysis, mOS and %ORR had moderate correlation in all comparisons (R<sup>2</sup>=0.58), in ICIs+ChT (R<sup>2</sup>=0.58) or ICIs (R<sup>2</sup>=0.53). In trial-level analysis, OR<sub>ORR</sub> and HR<sub>OS</sub> had moderate correlation (R<sup>2</sup>=0.55) in first-line setting and a strong correlation in ICIs+ChT trials (R<sup>2</sup>=0.79).</div></div><div><h3>Conclusions</h3><div>Across trials investigating ICIs in advanced NSCLC, PFS and ORR demonstrated various degrees of relationship with OS. Caution should be taken when efficacy of novel ICIs regimens is evaluated only using surrogate outcomes.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105092"},"PeriodicalIF":5.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cervical cancer (CC) is the fourth most common malignancy among women worldwide, highlighting the urgent need for improved predictive, diagnostic and prognostic biomarkers to enhance disease management and patient outcomes. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs), perform various functions in transcriptional, translational and post-translational regulation. Aberrant expression of ncRNAs in CC has been closely associated with disease initiation and progression, underscoring their potential as key regulators of cervical tumorigenesis. Several lncRNAs, such as HOTAIR and PVT1, contribute to cervical tumorigenesis by promoting cell proliferation, migration and invasion. Likewise, circRNAs, such as circ_0018289, act as miRNA sponges, leading to the dysregulation of key target genes. Moreover, specific miRNAs, such as miR-20a and miR-21, promote CC progression (oncogenic miRNAs), whereas others, including miR-214 and miR-218, exhibit a tumor suppressor role. Importantly, many ncRNAs are detectable in body fluids, representing stable and minimally invasive biomarkers suitable for liquid biopsy. Thus, in this comprehensive narrative review, we map the range of candidate ncRNAs reported in the literature and discuss their predictive, diagnostic, prognostic and therapeutic value, including their potential as circulating biomarkers in CC. We also highlight, as a future perspective, how integrated profiling approaches could guide research and support the development of non-invasive strategies for diagnosis, prognostic assessment, and therapy monitoring in CC.
{"title":"Non-coding RNAs and liquid biopsies: Emerging biomarkers for cervical cancer","authors":"Mariana Teixeira Costa , Valéria Tavares , Filomena Adega , Rui Medeiros","doi":"10.1016/j.critrevonc.2025.105091","DOIUrl":"10.1016/j.critrevonc.2025.105091","url":null,"abstract":"<div><div>Cervical cancer (CC) is the fourth most common malignancy among women worldwide, highlighting the urgent need for improved predictive, diagnostic and prognostic biomarkers to enhance disease management and patient outcomes. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs), perform various functions in transcriptional, translational and post-translational regulation. Aberrant expression of ncRNAs in CC has been closely associated with disease initiation and progression, underscoring their potential as key regulators of cervical tumorigenesis. Several lncRNAs, such as HOTAIR and PVT1, contribute to cervical tumorigenesis by promoting cell proliferation, migration and invasion. Likewise, circRNAs, such as circ_0018289, act as miRNA sponges, leading to the dysregulation of key target genes. Moreover, specific miRNAs, such as miR-20a and miR-21, promote CC progression (oncogenic miRNAs), whereas others, including miR-214 and miR-218, exhibit a tumor suppressor role. Importantly, many ncRNAs are detectable in body fluids, representing stable and minimally invasive biomarkers suitable for liquid biopsy. Thus, in this comprehensive narrative review, we map the range of candidate ncRNAs reported in the literature and discuss their predictive, diagnostic, prognostic and therapeutic value, including their potential as circulating biomarkers in CC. We also highlight, as a future perspective, how integrated profiling approaches could guide research and support the development of non-invasive strategies for diagnosis, prognostic assessment, and therapy monitoring in CC.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105091"},"PeriodicalIF":5.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-14DOI: 10.1016/j.critrevonc.2025.105086
Chuanjian Wu , Hanzhang Liu , Yujie Shi , Jie Tang , Rong Sun , Xudong Han , Yihui Fan
Oncolytic viruses (OVs) elicit potent tumor lysis and remodel the tumor microenvironment (TME) to activate adaptive and innate immunity, yet their efficacy depends critically on T and NK cell responses. Here, we review recent advances in the characterization and engineering of OVs to enhance lymphocyte-mediated tumor control. CD8⁺ cytotoxic T cells and CD4⁺ helper T cells drive durable antitumor immunity through OV-enhanced antigen presentation, memory formation, and modulation of Tregs, whereas T cell exhaustion and checkpoint interactions remain key barriers. Arming OVs with cytokines, chemokines, bispecific engagers, or metabolic modulators enhances effector T-cell expansion, infiltration, and cytotoxicity in solid tumors. In parallel, NK cells—whose efficacy is often limited by poor intratumoral activity and antiviral competition—are increasingly harnessed by OV platforms expressing immune stimulators or checkpoint modulators. Combination strategies with targeted therapies, checkpoint blockade, or adoptive NK/T cell transfer further potentiate therapeutic efficacy. Importantly, although OVs may inadvertently amplify dominant antiviral responses at the expense of antitumor activity, strategies incorporating tumor antigen encoding and TME reprogramming can overcome this limitation. Collectively, these findings underscore the central role of T and NK cells in OV-based immunotherapy and highlight rational arming and combination approaches to improve tumor control and long-term protection.
{"title":"Potential strategies to improve the therapeutic efficacy of oncolytic viruses for cancer through T and NK cells targeting","authors":"Chuanjian Wu , Hanzhang Liu , Yujie Shi , Jie Tang , Rong Sun , Xudong Han , Yihui Fan","doi":"10.1016/j.critrevonc.2025.105086","DOIUrl":"10.1016/j.critrevonc.2025.105086","url":null,"abstract":"<div><div>Oncolytic viruses (OVs) elicit potent tumor lysis and remodel the tumor microenvironment (TME) to activate adaptive and innate immunity, yet their efficacy depends critically on T and NK cell responses. Here, we review recent advances in the characterization and engineering of OVs to enhance lymphocyte-mediated tumor control. CD8⁺ cytotoxic T cells and CD4⁺ helper T cells drive durable antitumor immunity through OV-enhanced antigen presentation, memory formation, and modulation of Tregs, whereas T cell exhaustion and checkpoint interactions remain key barriers. Arming OVs with cytokines, chemokines, bispecific engagers, or metabolic modulators enhances effector T-cell expansion, infiltration, and cytotoxicity in solid tumors. In parallel, NK cells—whose efficacy is often limited by poor intratumoral activity and antiviral competition—are increasingly harnessed by OV platforms expressing immune stimulators or checkpoint modulators. Combination strategies with targeted therapies, checkpoint blockade, or adoptive NK/T cell transfer further potentiate therapeutic efficacy. Importantly, although OVs may inadvertently amplify dominant antiviral responses at the expense of antitumor activity, strategies incorporating tumor antigen encoding and TME reprogramming can overcome this limitation. Collectively, these findings underscore the central role of T and NK cells in OV-based immunotherapy and highlight rational arming and combination approaches to improve tumor control and long-term protection.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105086"},"PeriodicalIF":5.6,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genetic profiles alone do not fully describe the development and evolution of prostate cancer (PCa), whereas epigenetic alterations are emerging as promising therapeutic targets. This review explores FDA-approved and experimental epigenetic strategies, including DNA methyltransferase inhibitors (DNMTis), histone deacetylase inhibitors (HDACis), histone methyltransferase inhibitors, bromodomain and extra-terminal domain inhibitors (BETi), non-coding RNA therapies, antisense oligonucleotides, and future prospects such as chromatin remodeling, DNA hydroxymethylation, and RNA methylation. Although DNMTis and HDACis have historically dominated clinical trials, mainly in hematologic cancers, the 2020 approval of an epigenetic therapy for a solid tumor marked an important breakthrough. Despite this, epigenetic drugs remain underexplored in PCa: among 2254 clinical studies of such agents, only 58 (2.57 %) included PCa patients. This disparity highlights an urgent need for novel therapeutic approaches beyond chemotherapy and androgen deprivation. By assessing current progress and outlining opportunities in drug repositioning and novel targets, this review underscores epigenetics as a critical frontier for advancing PCa treatment.
{"title":"Epigenetic approaches to prostate cancer: Present landscape and future prospects","authors":"Konstantinos Mesiakaris, Efthalia Kontogianni, Souzana Logotheti, Vasiliki Tzelepi","doi":"10.1016/j.critrevonc.2025.105083","DOIUrl":"10.1016/j.critrevonc.2025.105083","url":null,"abstract":"<div><div>Genetic profiles alone do not fully describe the development and evolution of prostate cancer (PCa), whereas epigenetic alterations are emerging as promising therapeutic targets. This review explores FDA-approved and experimental epigenetic strategies, including DNA methyltransferase inhibitors (DNMTis), histone deacetylase inhibitors (HDACis), histone methyltransferase inhibitors, bromodomain and extra-terminal domain inhibitors (BETi), non-coding RNA therapies, antisense oligonucleotides, and future prospects such as chromatin remodeling, DNA hydroxymethylation, and RNA methylation. Although DNMTis and HDACis have historically dominated clinical trials, mainly in hematologic cancers, the 2020 approval of an epigenetic therapy for a solid tumor marked an important breakthrough. Despite this, epigenetic drugs remain underexplored in PCa: among 2254 clinical studies of such agents, only 58 (2.57 %) included PCa patients. This disparity highlights an urgent need for novel therapeutic approaches beyond chemotherapy and androgen deprivation. By assessing current progress and outlining opportunities in drug repositioning and novel targets, this review underscores epigenetics as a critical frontier for advancing PCa treatment.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105083"},"PeriodicalIF":5.6,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-14DOI: 10.1016/j.critrevonc.2025.105089
Bart C.T. van de Laar , Daan J. Sikkenk , Gursah Kats-Ugurlu , Derk Jan A. de Groot , Wouter B. Nagengast , Esther C.J. Consten
Background
In colon cancer (CC), lymph node (LN) (micro)metastases determine the need for adjuvant chemotherapy. Routine single-section hematoxylin and eosin (H&E) may miss (micro)metastases, resulting in understaging. Histopathological ultrastaging using serial sectioning (SS) and immunohistochemistry (IHC) can improve metastasis detection, for example in the context of organ-preserving surgery using a sentinel lymph node (SLN) procedure. This review evaluates SS and IHC for detecting LN (micro)metastases and aims to identify the ultrastaging method with the highest detection rate. Isolated tumor cells were analyzed separately and were not considered indicative of nodal upstaging.
Methods
PubMed, Embase, and the Cochrane Library were searched. Studies were included if they evaluated histopathological ultrastaging alongside routine H&E in patients with CC and reported results separately. Risk of bias was assessed using QUADAS-2. Pooled proportions were calculated using random-effects models.
Results
Thirty studies (n = 1822 patients) using SS and IHC were included. In SLN studies (n = 23), 21 % (95 % CI: 12–31 %) of 1070 patients had LN (micro)metastases. Among node-positive patients, 25 % (95 % CI: 6.0–50 %) were identified only by SLN ultrastaging. The absolute benefit of ultrastaging in the total cohort was small, 3.0 % (95 % CI: 1.0–5.0 %), with moderate heterogeneity. In non-SLN studies (n = 7), ultrastaging of all LNs upstaged 6.0 % (95 % CI: 2.0–13 %) of 752 patients, with high heterogeneity. IHC identified only one additional micrometastasis beyond SS. Protocol heterogeneity was considerable.
Conclusion
Histopathological ultrastaging detects (micro)metastases, but its clinical impact on adjuvant chemotherapy benefit remains uncertain. Protocol standardization is needed, and the added value of IHC beyond SS appears minimal.
{"title":"Histopathological ultrastaging of mesocolic lymph nodes after colon cancer resection: A systematic review and meta-analysis","authors":"Bart C.T. van de Laar , Daan J. Sikkenk , Gursah Kats-Ugurlu , Derk Jan A. de Groot , Wouter B. Nagengast , Esther C.J. Consten","doi":"10.1016/j.critrevonc.2025.105089","DOIUrl":"10.1016/j.critrevonc.2025.105089","url":null,"abstract":"<div><h3>Background</h3><div>In colon cancer (CC), lymph node (LN) (micro)metastases determine the need for adjuvant chemotherapy. Routine single-section hematoxylin and eosin (H&E) may miss (micro)metastases, resulting in understaging. Histopathological ultrastaging using serial sectioning (SS) and immunohistochemistry (IHC) can improve metastasis detection, for example in the context of organ-preserving surgery using a sentinel lymph node (SLN) procedure. This review evaluates SS and IHC for detecting LN (micro)metastases and aims to identify the ultrastaging method with the highest detection rate. Isolated tumor cells were analyzed separately and were not considered indicative of nodal upstaging.</div></div><div><h3>Methods</h3><div>PubMed, Embase, and the Cochrane Library were searched. Studies were included if they evaluated histopathological ultrastaging alongside routine H&E in patients with CC and reported results separately. Risk of bias was assessed using QUADAS-2. Pooled proportions were calculated using random-effects models.</div></div><div><h3>Results</h3><div>Thirty studies (n = 1822 patients) using SS and IHC were included. In SLN studies (n = 23), 21 % (95 % CI: 12–31 %) of 1070 patients had LN (micro)metastases. Among node-positive patients, 25 % (95 % CI: 6.0–50 %) were identified only by SLN ultrastaging. The absolute benefit of ultrastaging in the total cohort was small, 3.0 % (95 % CI: 1.0–5.0 %), with moderate heterogeneity. In non-SLN studies (n = 7), ultrastaging of all LNs upstaged 6.0 % (95 % CI: 2.0–13 %) of 752 patients, with high heterogeneity. IHC identified only one additional micrometastasis beyond SS. Protocol heterogeneity was considerable.</div></div><div><h3>Conclusion</h3><div>Histopathological ultrastaging detects (micro)metastases, but its clinical impact on adjuvant chemotherapy benefit remains uncertain. Protocol standardization is needed, and the added value of IHC beyond SS appears minimal.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105089"},"PeriodicalIF":5.6,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic Myeloid Leukemia is driven by the BCR::ABL1 fusion gene, which transforms bone marrow stem cells. Tyrosine kinase inhibitors have markedly improved patients’ outcomes. However, only about 20 % of patients are cured, remaining free of relapses after the achievement of a profound and durable molecular remission of the disease and the suspension of tyrosine kinase inhibitors. In most cases, leukemic stem cells persist and contribute to disease relapse after treatment suspension or the development of acquired resistance to tyrosine kinase inhibitors. Emerging evidence underscores the pivotal role of the bone marrow microenvironment in sustaining leukemic stem cells and contributing to drug resistance. Stromal progenitor cells within the bone marrow niche play a key role in supporting the persistence and survival of resistant leukemic stem cells. This review examines how the bone marrow microenvironment and its components promote drug resistance through mechanisms such as metabolic reprogramming, aberrant signaling, and protective cellular interactions. These insights reveal potential therapeutic strategies aimed at disrupting the leukemic stem cell supportive niche to achieve more effective eradication of resistant clones. Understanding the complex interplay between leukemic stem cells and their microenvironment is crucial for developing targeted treatments that can overcome resistance and achieve long-term remission in patients with chronic myeloid leukemia.
{"title":"The role of the bone marrow microenvironment in leukemic stem cell resistance: Pathways of persistence and selection","authors":"Serena Barachini , Marina Montali , Irene Sofia Burzi , Eleonora Pardini , Gisella Sardo Infirri , Raffaella Cassano Cassano , Iacopo Petrini","doi":"10.1016/j.critrevonc.2025.105090","DOIUrl":"10.1016/j.critrevonc.2025.105090","url":null,"abstract":"<div><div>Chronic Myeloid Leukemia is driven by the BCR::ABL1 fusion gene, which transforms bone marrow stem cells. Tyrosine kinase inhibitors have markedly improved patients’ outcomes. However, only about 20 % of patients are cured, remaining free of relapses after the achievement of a profound and durable molecular remission of the disease and the suspension of tyrosine kinase inhibitors. In most cases, leukemic stem cells persist and contribute to disease relapse after treatment suspension or the development of acquired resistance to tyrosine kinase inhibitors. Emerging evidence underscores the pivotal role of the bone marrow microenvironment in sustaining leukemic stem cells and contributing to drug resistance. Stromal progenitor cells within the bone marrow niche play a key role in supporting the persistence and survival of resistant leukemic stem cells. This review examines how the bone marrow microenvironment and its components promote drug resistance through mechanisms such as metabolic reprogramming, aberrant signaling, and protective cellular interactions. These insights reveal potential therapeutic strategies aimed at disrupting the leukemic stem cell supportive niche to achieve more effective eradication of resistant clones. Understanding the complex interplay between leukemic stem cells and their microenvironment is crucial for developing targeted treatments that can overcome resistance and achieve long-term remission in patients with chronic myeloid leukemia.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105090"},"PeriodicalIF":5.6,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.critrevonc.2025.105084
R. Swathika , Yogendra Nayak , Bharath Prasad AS , Usha Yogendra Nayak
Melanoma, an aggressive and frequently treatment-resistant kind of skin cancer, poses substantial therapeutic hurdles, especially because it is resistant to inhibitors of the MAPK (mitogen-activated protein kinase) pathway. Even though targeted therapies like BRAF and MEK inhibitors are advanced melanoma therapies, tumour cell plasticity and TME interactions can lead to resistance. Recent research demonstrates that CAFs play a role in fibrotic remodelling in the TME, which promotes tumour growth, immunological suppression, and treatment resistance. Stiffening of ECM because of the pro-fibrotic and pro-tumorigenic substances secreted by CAFs. This, in turn, activates survival pathways and fosters treatment resistance. Anti-fibrotic drugs are meant to treat fibrotic conditions, including idiopathic pulmonary fibrosis, but because of their ability to alter ECM structure and prevent fibroblast activation, they have recently attracted interest in oncology. Targeting fibrotic pathways such as TGF-β, FGF, and PDGF signalling, with medications like nintedanib and pirfenidone, may help overcome the resistance mechanisms associated with MAPK inhibitor therapy. Through the disruption of stromal signalling and the reduction of stress caused by fibrosis, these medicines have the potential to improve drug penetration, decrease tumour plasticity, and restore sensitivity to treatments that target MAPK. This review unravels the complex interactions between MAPK inhibitors and anti-fibrotic drugs in the treatment of melanoma, highlighting how they might work together to remodel the TME and overcome treatment resistance. Implementing this combinatorial method could lead to novel approaches for long-term melanoma control and provide a model for anti-fibrotic-based treatments for other solid cancers.
{"title":"Unravelling the crosstalk: Anti-fibrotic agents and MAPK inhibitors in the treatment of melanoma","authors":"R. Swathika , Yogendra Nayak , Bharath Prasad AS , Usha Yogendra Nayak","doi":"10.1016/j.critrevonc.2025.105084","DOIUrl":"10.1016/j.critrevonc.2025.105084","url":null,"abstract":"<div><div>Melanoma, an aggressive and frequently treatment-resistant kind of skin cancer, poses substantial therapeutic hurdles, especially because it is resistant to inhibitors of the MAPK (mitogen-activated protein kinase) pathway. Even though targeted therapies like BRAF and MEK inhibitors are advanced melanoma therapies, tumour cell plasticity and TME interactions can lead to resistance. Recent research demonstrates that CAFs play a role in fibrotic remodelling in the TME, which promotes tumour growth, immunological suppression, and treatment resistance. Stiffening of ECM because of the pro-fibrotic and pro-tumorigenic substances secreted by CAFs. This, in turn, activates survival pathways and fosters treatment resistance. Anti-fibrotic drugs are meant to treat fibrotic conditions, including idiopathic pulmonary fibrosis, but because of their ability to alter ECM structure and prevent fibroblast activation, they have recently attracted interest in oncology. Targeting fibrotic pathways such as TGF-β, FGF, and PDGF signalling, with medications like nintedanib and pirfenidone, may help overcome the resistance mechanisms associated with MAPK inhibitor therapy. Through the disruption of stromal signalling and the reduction of stress caused by fibrosis, these medicines have the potential to improve drug penetration, decrease tumour plasticity, and restore sensitivity to treatments that target MAPK. This review unravels the complex interactions between MAPK inhibitors and anti-fibrotic drugs in the treatment of melanoma, highlighting how they might work together to remodel the TME and overcome treatment resistance. Implementing this combinatorial method could lead to novel approaches for long-term melanoma control and provide a model for anti-fibrotic-based treatments for other solid cancers.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105084"},"PeriodicalIF":5.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.critrevonc.2025.105088
Hatice Bölek , Mine Araz , Cigdem Soydal , Emre Yekedüz , Nuriye Özlem Küçük , Yüksel Ürün
Background
The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved with the introduction of novel therapies, including targeted radioligand therapies (RLTs). However, data about sequential use of RLT remains limited.
Objective
This study aims to present a case report on the sequential use of RLTs and to investigate the efficacy of administering different RLTs in sequence.
Methods
A systematic review of the literature was conducted following PRISMA guidelines. Studies reporting on patients who received sequential RLT agents for mCRPC and included efficacy data for the subsequent agent were included in the study.
Results
A total of 16 studies met the inclusion criteria. Among these, nine studies reported the use of Lutetium-177 PSMA (¹⁷⁷Lu‑PSMA) following Radium-223 (223Ra), seven studies reported Actinium‑225 PSMA (²²⁵Ac‑PSMA) after ¹ ⁷⁷Lu‑PSMA, two studies reported ²²⁵Ac‑PSMA following 223Ra, and one study investigated Terbium-161 PSMA (¹⁶¹Tb‑PSMA) after ¹ ⁷⁷Lu‑PSMA. For patients receiving ¹ ⁷⁷Lu‑PSMA following 223Ra, the reported median progression-free survival (PFS) ranged from 3 to 10 months, while overall survival (OS) ranged from 11.1 to 18 months. In those treated with ²²⁵Ac‑PSMA after prior ¹ ⁷⁷Lu‑PSMA, the median PFS ranged from 3.1 to 10 months, and OS ranged from 7.7 to 16 months. Treatment was generally well tolerated; hematologic toxicities were the most reported adverse events.
Conclusion
Sequential administration of RLTs may provide sustained clinical benefit in patients with mCRPC. However, the existing evidence is limited, heterogeneous, and predominantly derived from retrospective analyses.
{"title":"Sequential use of targeted radioligand therapies in metastatic castration-resistant prostate cancer: A case report and systematic review","authors":"Hatice Bölek , Mine Araz , Cigdem Soydal , Emre Yekedüz , Nuriye Özlem Küçük , Yüksel Ürün","doi":"10.1016/j.critrevonc.2025.105088","DOIUrl":"10.1016/j.critrevonc.2025.105088","url":null,"abstract":"<div><h3>Background</h3><div>The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved with the introduction of novel therapies, including targeted radioligand therapies (RLTs). However, data about sequential use of RLT remains limited.</div></div><div><h3>Objective</h3><div>This study aims to present a case report on the sequential use of RLTs and to investigate the efficacy of administering different RLTs in sequence.</div></div><div><h3>Methods</h3><div>A systematic review of the literature was conducted following PRISMA guidelines. Studies reporting on patients who received sequential RLT agents for mCRPC and included efficacy data for the subsequent agent were included in the study.</div></div><div><h3>Results</h3><div>A total of 16 studies met the inclusion criteria. Among these, nine studies reported the use of Lutetium-177 PSMA (¹⁷⁷Lu‑PSMA) following Radium-223 (<sup>223</sup>Ra), seven studies reported Actinium‑225 PSMA (²²⁵Ac‑PSMA) after ¹ ⁷⁷Lu‑PSMA, two studies reported ²²⁵Ac‑PSMA following <sup>223</sup>Ra, and one study investigated Terbium-161 PSMA (¹⁶¹Tb‑PSMA) after ¹ ⁷⁷Lu‑PSMA. For patients receiving ¹ ⁷⁷Lu‑PSMA following <sup>223</sup>Ra, the reported median progression-free survival (PFS) ranged from 3 to 10 months, while overall survival (OS) ranged from 11.1 to 18 months. In those treated with ²²⁵Ac‑PSMA after prior ¹ ⁷⁷Lu‑PSMA, the median PFS ranged from 3.1 to 10 months, and OS ranged from 7.7 to 16 months. Treatment was generally well tolerated; hematologic toxicities were the most reported adverse events.</div></div><div><h3>Conclusion</h3><div>Sequential administration of RLTs may provide sustained clinical benefit in patients with mCRPC. However, the existing evidence is limited, heterogeneous, and predominantly derived from retrospective analyses.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105088"},"PeriodicalIF":5.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bacteriophage therapy has re-emerged as a rapidly advancing field in oncology, bridging antimicrobial precision with tumor-targeted biotherapy. Beyond infection control, phages are now recognized as programmable biological systems capable of eradicating multidrug-resistant (MDR) pathogens, modulating tumor-associated microbiota, activating immune responses, and delivering therapeutic genes or drugs. Preclinical evidence shows that phages can selectively eliminate Fusobacterium nucleatum in oral squamous cell carcinoma, restore microbial balance in colorectal cancer, and enhance immune infiltration via cytokine or antigen display. Engineered constructs including GM-CSF–expressing and MAGE-A1–displaying phages, λ-phage ASPH vaccines, and PEGylated nanocarriers delivering MEG3 or TRAIL have demonstrated strong anti-tumor efficacy across melanoma, hepatocellular, and colorectal cancer models. Additionally, CRISPR–Cas–armed phages precisely remove resistance genes such as bla-CTX-M and mecA, while AI-driven selection pipelines enable data-guided design of personalized phage cocktails. These advances represent a paradigm shift from empirical antibacterial use toward mechanistically engineered, multifunctional phage platforms that integrate microbiome modulation, immune activation, and nanocarrier-mediated gene delivery. Although challenges such as immune clearance, bacterial resistance, and regulatory complexity remain, the convergence of AI, CRISPR, and synthetic biology is accelerating the evolution of phage therapy into a clinically viable precision-oncology strategy. In this context, bacteriophages emerge not merely as antibacterial agents but as intelligent, patient-specific nanomedicines poised to redefine therapeutic boundaries in cancer treatment.
{"title":"Phage therapy in cancer treatment: Mechanisms, emerging innovations, and translational progress","authors":"Chou-Yi Hsu , Djamila Polatova , Rania Hameed Hamad , Pareshkumar N. Patel , Muhammad Akram , Gunjan Singh , Vimal Arora , Priya Priyadarshini Nayak , Munthar Kadhem , Hamza Fadhel Hamzah","doi":"10.1016/j.critrevonc.2025.105085","DOIUrl":"10.1016/j.critrevonc.2025.105085","url":null,"abstract":"<div><div>Bacteriophage therapy has re-emerged as a rapidly advancing field in oncology, bridging antimicrobial precision with tumor-targeted biotherapy. Beyond infection control, phages are now recognized as programmable biological systems capable of eradicating multidrug-resistant (MDR) pathogens, modulating tumor-associated microbiota, activating immune responses, and delivering therapeutic genes or drugs. Preclinical evidence shows that phages can selectively eliminate <em>Fusobacterium nucleatum</em> in oral squamous cell carcinoma, restore microbial balance in colorectal cancer, and enhance immune infiltration via cytokine or antigen display. Engineered constructs including GM-CSF–expressing and MAGE-A1–displaying phages, λ-phage ASPH vaccines, and PEGylated nanocarriers delivering MEG3 or TRAIL have demonstrated strong anti-tumor efficacy across melanoma, hepatocellular, and colorectal cancer models. Additionally, CRISPR–Cas–armed phages precisely remove resistance genes such as <em>bla</em>-CTX-M and <em>mecA</em>, while AI-driven selection pipelines enable data-guided design of personalized phage cocktails. These advances represent a paradigm shift from empirical antibacterial use toward mechanistically engineered, multifunctional phage platforms that integrate microbiome modulation, immune activation, and nanocarrier-mediated gene delivery. Although challenges such as immune clearance, bacterial resistance, and regulatory complexity remain, the convergence of AI, CRISPR, and synthetic biology is accelerating the evolution of phage therapy into a clinically viable precision-oncology strategy. In this context, bacteriophages emerge not merely as antibacterial agents but as intelligent, patient-specific nanomedicines poised to redefine therapeutic boundaries in cancer treatment.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105085"},"PeriodicalIF":5.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1016/j.critrevonc.2025.105079
Dadi Shu , Zhaoming Chen , Baolin Li , Jing Wei , Jinbo Liu , Qiongying Hu
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and ranks third in incidence among all cancer types. Among the treatment strategies for CRC, immunotherapy—particularly approaches targeting modulation of the tumor microenvironment (TME) to prevent immune escape—represents a key component. The interaction and influence between CRC cells and tumor-associated macrophages (TAMs) within the TME have been shown to be closely associated with immune escape and malignant progression in CRC. Among them, extracellular vesicles (EVs) derived from CRC cells (CRC-EVs) can be taken up by TAMs in the TME and regulate their polarization as well as the production of related bioactive substances. Conversely, EVs secreted by TAMs (TAMs-EVs) can be internalized by CRC cells, thereby promoting the malignant biological behaviors, including proliferation, metastasis, and resistance to radiotherapy and chemotherapy. In this review, we focus on the crosstalk between CRC cells and TAMs within the TME, summarizing and integrating current evidence on how CRC-EVs and TAMs-EVs contribute to TME remodeling and thereby influence CRC malignancy, while systematically outlining the cellular signaling pathways involved in this bidirectional communication.
{"title":"Crosstalk between tumor cells and tumor-associated macrophages mediated by extracellular vesicles: Research advances in remodeling the tumor microenvironment in colorectal cancer","authors":"Dadi Shu , Zhaoming Chen , Baolin Li , Jing Wei , Jinbo Liu , Qiongying Hu","doi":"10.1016/j.critrevonc.2025.105079","DOIUrl":"10.1016/j.critrevonc.2025.105079","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and ranks third in incidence among all cancer types. Among the treatment strategies for CRC, immunotherapy—particularly approaches targeting modulation of the tumor microenvironment (TME) to prevent immune escape—represents a key component. The interaction and influence between CRC cells and tumor-associated macrophages (TAMs) within the TME have been shown to be closely associated with immune escape and malignant progression in CRC. Among them, extracellular vesicles (EVs) derived from CRC cells (CRC-EVs) can be taken up by TAMs in the TME and regulate their polarization as well as the production of related bioactive substances. Conversely, EVs secreted by TAMs (TAMs-EVs) can be internalized by CRC cells, thereby promoting the malignant biological behaviors, including proliferation, metastasis, and resistance to radiotherapy and chemotherapy. In this review, we focus on the crosstalk between CRC cells and TAMs within the TME, summarizing and integrating current evidence on how CRC-EVs and TAMs-EVs contribute to TME remodeling and thereby influence CRC malignancy, while systematically outlining the cellular signaling pathways involved in this bidirectional communication.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105079"},"PeriodicalIF":5.6,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145758643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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