Submit to Cancers Review for Cancers Propose a Special Issue

Journal Menu

Journal Browser

► Journal Browser

Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition)

Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2025) | Viewed by 18194

Share This Special Issue

Special Issue Editors

Dr. Santosh Kumar Singh

E-Mail Website
Guest Editor

Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
Interests: cancer; drug resistance; natural compound; targeted therapy; drug delivery
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Rajesh Singh

E-Mail Website
Guest Editor

Department of Microbiology, Immunology and Biochemistry, Morehouse School of Medicine, Atlanta, GA 30310, USA
Interests: cancer immunobiology; health disparity; drug discovery; precision oncology; nanotechnology; chemokines
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent decades, concerns regarding cancer have grown rapidly. Many cancer screening programs are being implemented in high-and middle-income countries to reduce the incidence and mortality of cancer. However, the yearly rise in cases is disappointing considering the extensive use of various therapeutic approaches. Emerging evidence suggests that drug resistance and relapse also represent significant issues during treatment. Therefore, no single breakthrough can cure cancer; however, accumulating knowledge regarding the complex mechanisms implicated in the pathogenesis of cancer could reduce the associated mortality rate. Thus, understanding signaling pathways and developing novel targeted techniques, including molecular, biochemical, immunological, and nanotherapy, may provide clinicians searching for new targets for treatment with hope.

To address these challenges, this Special Issue aims to present novel targeted therapies and their underlying mechanism. The scope of this Special Issue therefore includes, but is not limited to, the following topics: natural compound combination therapy, chemotherapy, immunotherapy, and nanotherapy. We welcome you to submit original research and review articles that address recent advances in this field.

Dr. Rajesh Singh
Dr. Santosh Kumar Singh
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cancer
anticancer therapy
combination therapy
natural compound
nanotherapy
exosome therapy
targeted therapy
immunotherapy
chemokines
cytokines
antibodies
drug resistance

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
Reprint: MDPI Books provides the opportunity to republish successful Special Issues in book format, both online and in print.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (8 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

22 pages, 2109 KB

Open AccessArticle

Pharmacologic and Oncohistone Inhibition of SETD2 Converge on Genomic Instability

by Alyssa T. Paparella, Ashley G. Boice, In Young Park, Rajkishor Nishad, Durga Tripathi, Seth A. Nelson, Edward W. Pietryk, H. Josh Jang, Ian J. Frew, W. Kimryn Rathmell, Frank M. Mason, Cristian Coarfa, Ruhee Dere and Cheryl Lyn Walker

Cancers 2026, 18(5), 819; https://doi.org/10.3390/cancers18050819 - 3 Mar 2026

Viewed by 926

Abstract

Background/Objectives: SETD2 is a dual-function methyltransferase important for methylation of histone H3 at lysine 36 and α-tubulin in spindle microtubules. Genetic inactivation of SETD2 during oncogenesis drives loss of H3K36me3, genomic instability, and cancer progression. This study asked if disruption of genomic stability was a canonical feature of SETD2 inactivation via different pathways. Methods: We evaluated the impact of EPZ-719, a pharmacologic SETD2 inhibitor, and an H3.3K36M mutant histone (“oncohistone”) that binds and sequesters SETD2, on methylation activity and genomic stability in human cell lines. SETD2 activity was measured using in vitro methylation assays, H3K36me3 loss confirmed by Western analysis, and mitotic defects, specifically micronuclei and chromatin bridges, quantified with cytogenetic analysis. Results: EPZ-719 caused a dose- and time-dependent reduction in SETD2 activity on both histone and tubulin substrates, accompanied by significant increases in chromatin bridges and micronuclei in retinal pigmented epithelial (RPE-1) and 786-O ccRCC cells. Similarly, oncohistone expression markedly decreased SETD2 function, as determined by H3K36me3 levels, and induced comparable mitotic defects in 786-O cells, and aneuploidy in two chondrocyte cell lines expressing the H3.3K36M oncohistone. Combining EPZ-719 with H3.3K36M expression did not exacerbate mitotic defects beyond either oncohistone or pharmacologic inhibition alone, consistent with inhibition of SETD2 as their shared underlying mechanism of action. Conclusions: Pharmacologic inhibition and oncohistone-mediated sequestration of SETD2 converge on the induction of mitotic defects, underscoring SETD2’s essential role in maintaining genomic stability. Identification of loss of genomic stability as a canonical feature of SETD2 inactivation points to a potential therapeutic liability associated with targeting SETD2 in cancers where it is overexpressed and reveals a mechanism that could contribute to the progression of cancers expressing oncohistone mutations. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition))

► Show Figures

Graphical abstract

27 pages, 2246 KB

Open AccessArticle

Harnessing Postbiotics to Boost Chemotherapy: N-Acetylcysteine and Tetrahydro β-Carboline Carboxylic Acid as Potentiators in Pancreatic and Colorectal Cancer

by Vanessa Rodriguez, Annacandida Villani, Margarida Sénica, Concetta Panebianco, Valerio Pazienza and Ana Preto

Cancers 2026, 18(3), 369; https://doi.org/10.3390/cancers18030369 - 25 Jan 2026

Viewed by 712

Abstract

Background: Pancreatic cancer (PC) and colorectal cancer (CRC) are among the most lethal malignancies, with growing evidence pointing to the gut microbiota’s role in their progression. This study aimed to explore the anticancer potential of two microbiota-derived postbiotics, N-acetylcysteine (NAC) and tetrahydro β-carboline carboxylic acid (THC), in targeting some hallmark traits of PC and CRC, both as standalone agents and in combination with standard chemotherapeutics (gemcitabine for PC and 5-fluorouracil (5-FU) for CRC). Methods: Cell viability assays and IC₅₀ determination was assessed using either the Muse™ Count & Viability Kit or the Sulforhodamine B assay; cell death was determined by Annexin V/Propidium Iodide and cell cycle assessed by Propidium Iodide was analyzed by flow cytometry. Results: Here, we found that NAC selectively reduced the viability of PC cells BxPC-3 without triggering apoptosis, while effectively inducing apoptosis in PC cells Panc-1 and in CRC cell lines. THC exhibited stronger anticancer activity, inhibiting proliferation and promoting apoptosis in all tested PC and CRC cells, even at lower concentrations. Combination treatments yielded promising enhancement effects. NAC enhanced the cytotoxicity of gemcitabine in Panc-1 cells through increased apoptosis. NAC, when combined with 5-FU, also increased apoptosis of CRC cells. THC further potentiated gemcitabine’s impact on Panc-1 cells by increasing apoptosis and by inducing cell cycle changes in BxPC-3. In the CRC model, THC co-treatment with 5-FU reduced cell viability and increased apoptosis in all cells. Conclusions: These findings provide preliminary in vitro evidence supporting the potential of integrating microbiota-derived postbiotics with conventional chemotherapy both in PC and CRC. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition))

► Show Figures

Figure 1

23 pages, 2349 KB

Open AccessArticle

Artemis (DCLRE1C) Acts as a Target to Enhance Radiotherapy Response in Triple-Negative Breast Cancer

by Vasudeva Bhat, Kelsie L. Thu, Anayra de Fatima Goncalves Santiago, Anna C. Bonvissuto, Farhad Ghasemi, David Goodale, Michael V. Roes, Daniel T. Passos, Frederick A. Dick, David W. Cescon, Alison L. Allan and Armen Parsyan

Cancers 2025, 17(20), 3279; https://doi.org/10.3390/cancers17203279 - 10 Oct 2025

Viewed by 1705

Abstract

Background/Objectives: The lack of canonical biomarkers and strategies to target radioresistance contribute to poor patient outcomes in triple-negative breast cancer (TNBC). Identifying and targeting novel radioresistance genes will benefit in enhancing radiotherapy response and treatment outcomes in TNBC patients. Methods: A genome-wide CRISPR screen was performed to identify radioresistance genes in the TNBC cell line. An in vitro clonogenic assay was used to assess the antiproliferative effects of Artemis knockout or pharmacologic inhibition of Artemis, either alone or in combination with RT. Tumor doubling time and animal survival were assessed using an in vivo xenograft model. RNA-seq analysis was performed to identify genes and pathways deregulated under Artemis knockout conditions, both alone and in combination with RT. Cellular senescence was evaluated using a β-galactosidase assay. Results: Our CRISPR screen identified Artemis as a top hit in RT-treated TNBC cells, whose depletion led to radiosensitization in TNBC. Artemis knockout significantly reduced cell proliferation and enhanced the antiproliferative effects of RT in vitro. Compared to mice-bearing control MDA-MB-231 xenografts, Artemis knockout exhibited prolonged survival that was further enhanced with RT. Bulk RNA-sequencing indicated that the antiproliferative and radiosensitization effects of Artemis depletion were mediated by the activation of cellular senescence which was confirmed with a β-galactosidase assay. Conclusions: Taken together, our results highlight the critical role of Artemis in TNBC cell proliferation and response to radiation. Our findings identify Artemis as a potential biomarker indicative of sensitivity to radiation and a putative target that could be inhibited to enhance the efficacy of RT in TNBC. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition))

► Show Figures

Figure 1

15 pages, 1957 KB

Open AccessArticle

Association of TP53 with Defective Long Chain 3-Hydroxy acyl-CoA Dehydrogenase Induced Non-Cirrhotic Hepatocellular Carcinoma

by Tripti Khare, Alexei J. Stuckel, Suneel Gupta, Karina Liu, Ghassan M. Hammoud, Jamal A. Ibdah and Sharad Khare

Cancers 2025, 17(19), 3241; https://doi.org/10.3390/cancers17193241 - 6 Oct 2025

Viewed by 1396

Abstract

Background and Aims: Little is known about metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocellular carcinoma (HCC) in non-cirrhotic (HCC-NC) patients. In-house developed mouse models with defective lipid-metabolizing enzyme long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD), coded by hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) gene, result in MASLD (steatosis) without cirrhosis leading to HCC-NC. The aims of the current investigations are to assess molecular markers and the associated molecular events that may lead to HCC-NC. Methods: cDNA array study of HCC patients was conducted to assess the expression of HADHA transcripts. Differentially expressed proteins identified between wild-type (WT) and heterozygous mice with no cancer (HT) from a previous study were subjected to Ingenuity Pathway Analysis (IPA). Western blotting was performed to assess the expression of proteins. Results: IPA of the differentially expressed proteins between WT and HT mice results in two biological networks (network 1 and network 2), which pointed to an important role of p53 in HCC-NC. Validation of the levels of MDM2 and p53 also highlights the role of MDM2-p53 axis in HCC-NC. All the focus molecules in network 1 and network 2 are either presented as tumor suppressor/promoter of carcinogenesis or serum markers for early HCC diagnosis. The hepatotoxicity report from IPA further identified four functional groups including liver steatosis, glutathione depletion, hepatocellular carcinoma, and liver hyperplasia/hyperproliferation. Conclusions: This study suggests that impaired fatty oxidation may play a role in the development of HCC associated with steatosis but without cirrhosis (HCC-NC). Defective LCHAD is a novel etiology for HCC. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition))

► Show Figures

Figure 1

15 pages, 4053 KB

Open AccessArticle

Analysis of the Role of the SRC Tyrosine Kinase and Podoplanin in the Process of Entosis

by Agata M. Gawel, Marlena Godlewska, Lukasz P. Biały and Izabela Mlynarczuk-Bialy

Cancers 2025, 17(19), 3173; https://doi.org/10.3390/cancers17193173 - 29 Sep 2025

Viewed by 949

Abstract

Background: Over the last years, the phenomenon of entosis, a form of cell-in-cell structure, has been highlighted in various tumors, including poorly treatable breast or pancreatic cancers. Nevertheless, not only the biological properties, but also the molecular drivers of entosis remain unclear. Here, we evaluated SRC tyrosine kinase, a key proto-oncogene, and podoplanin (PDPN), a membrane glycoprotein, as potential regulators of entotic cell formation. Methods: In the study, two entosis-competent cell lines, BxPC-3 and MFC-7, originating from pancreatic and breast cancers, respectively, were used. SRC or PDPN genes were silenced using dedicated siRNA and the frequency of entotic structure formation was assessed using fluorescent staining and confocal imaging. Results: It was found that BxPC-3 cells deficient in PDPN are more prone to form entotic structures and that over 90% of all entotic figures formed by mixed PDPN⁺ and PDPN^- BxPC-3 cells involved PDPN-silenced cells. The SRC data supports this observation, as the suppressed entotic formation ability presented by SRC-deficient cells was linked with increased expression of PDPN. Even though the observed effects were mainly limited to BxPC-3 cells, as PDPN expression in MCF-7 cells is restricted, overall, the obtained data suggest a strong anti-entotic function of PDPN. Additionally, the performed Western blotting indicated the activation of ezrin-radixin-moesin (ERM) proteins in PDPN-deficient cells. Conclusions: Taken together, these data suggest that the negatively controlled PDPN-ERM axis may act as a molecular factor controlling the development of entotic structures and cells with naturally low PDPN expression may be more liable to form entoses. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition))

► Show Figures

Graphical abstract

12 pages, 2243 KB

Open AccessArticle

Cholinergic Receptor Nicotinic Beta 2 Subunit Promotes the Peritoneal Disseminating Metastasis of Colorectal Cancer

by Shinichi Umeda, Kenshiro Tanaka, Takayoshi Kishida, Norifumi Hattori, Haruyoshi Tanaka, Dai Shimizu, Hideki Takami, Masamichi Hayashi, Chie Tanaka, Goro Nakayama and Mitsuro Kanda

Cancers 2025, 17(15), 2485; https://doi.org/10.3390/cancers17152485 - 28 Jul 2025

Viewed by 849

Abstract

Background: Peritoneal dissemination in colorectal cancer (CRC) is associated with poor prognosis due to limited efficacy of current therapeutic strategies. The cholinergic receptor nicotinic beta 2 subunit (CHRNB2), a component of the acetylcholine receptor, has been implicated in other malignancies, but its role in CRC remains unknown. Methods: This study evaluated the expression and function of CHRNB2 in CRC. CHRNB2 mRNA levels were quantified by qRT-PCR in cell lines and clinical specimens. Functional assays were conducted using CRC cell lines with high CHRNB2 expression, in which CHRNB2 was knocked down by shRNA. Cell proliferation, migration, and invasion were assessed in vitro. In vivo effects were evaluated using subcutaneous and peritoneal xenograft models. The impact of CHRNB2 monoclonal antibody (mAb) treatment on CRC cell proliferation was also examined. Clinical correlations were assessed between CHRNB2 expression and clinicopathological features, including recurrence patterns. Results: CHRNB2 expression varied among CRC cell lines, with the highest levels observed in LOVO cells. CHRNB2 knockdown significantly inhibited proliferation, migration, and invasion in vitro and suppressed tumor growth in vivo. CHRNB2 mAb treatment reduced cell proliferation. Clinically, high CHRNB2 expression correlated with a significantly higher cumulative rate of peritoneal recurrence, but not with recurrence in the liver, lungs, or lymph nodes. Multivariate analysis identified high CHRNB2 expression and T4 tumor depth as independent predictors of peritoneal recurrence. Conclusions: CHRNB2 promotes the malignant phenotype of CRC, particularly in peritoneal dissemination. These findings suggest that CHRNB2 may serve as a novel diagnostic biomarker and therapeutic target for CRC with peritoneal metastasis. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition))

► Show Figures

Figure 1

16 pages, 3131 KB

Open AccessArticle

Mesothelin-Associated Anti-Senescence Through P53 in Pancreatic Ductal Adenocarcinoma

by Dongliang Liu, Jianming Lu, Changyi Chen and Qizhi Yao

Cancers 2025, 17(12), 2058; https://doi.org/10.3390/cancers17122058 - 19 Jun 2025

Cited by 3 | Viewed by 1949

Abstract

Objectives: Mesothelin (MSLN) is overexpressed in pancreatic ductal adenocarcinoma (PDAC), promoting cell proliferation, migration, and inhibiting apoptosis. While its oncogenic properties have been documented, the role of MSLN in regulating cellular senescence—a tumor-suppressive mechanism—has remained unexplored. This study is the first to identify and characterize a novel mesothelin-associated anti-senescence (MAAS) effect in PDAC. Methods: A proteogenomic analysis of PDAC tissue samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) was performed to evaluate MSLN-associated senescence pathways using WebGestalt. Human and murine PDAC cell lines with modified MSLN expression were analyzed for senescence phenotypes via SA-β-gal staining, Western blotting of key regulators (P53, P21^waf1, and P16^ink4a), γH2AX immunoblotting, and IL-8 quantification using ELISA. Results: The CPTAC analysis revealed an inverse correlation between MSLN expression and DNA damage/repair pathways. MSLN-deficient cells exhibited classic senescence features—growth arrest, an enlarged morphology, and elevated SA-β-gal activity. The expression of P53, P21^waf1, and P16^ink4a was upregulated, alongside increased γH2AX levels, indicating the activation of the DNA damage response. IL-8 secretion was significantly higher in the MSLN knockdown cells and reduced in the MSLN-overexpressing cells, consistent with the modulation of the SASP. Notably, MSLN deficiency impaired cell viability without inducing overt cytotoxicity, supporting a shift toward senescence. Conclusions: Our findings uncover a previously unrecognized mechanism through which MSLN promotes tumor progression by suppressing senescence via P53-associated pathways. Targeting the MAAS pathway may offer a novel therapeutic strategy to restore tumor-suppressive senescence and enhance treatment efficacy in PDAC. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition))

► Show Figures

Figure 1

Review

Jump to: Research

28 pages, 1534 KB

Open AccessEditor’s ChoiceReview

T-Cell Engager Therapy in Prostate Cancer: Molecular Insights into a New Frontier in Immunotherapy

by Whi-An Kwon and Jae Young Joung

Cancers 2025, 17(11), 1820; https://doi.org/10.3390/cancers17111820 - 29 May 2025

Cited by 10 | Viewed by 9054

Abstract

Advanced prostate cancer (PCa) remains lethal despite standard therapies, and immune checkpoint inhibitors offer limited benefit in its “immune-cold” microenvironment. T-cell engagers (TCEs)—bispecific antibodies linking CD3 on T-cells to tumor-associated antigens (TAAs)—provide potent, MHC-independent cytotoxicity, overcoming a key resistance mechanism. While early PSMA-targeted TCEs established proof-of-concept, recent data, notably for six transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeting agents like Xaluritamig, demonstrate more substantial objective responses, highlighting progress through improved target selection and molecular design. This review synthesizes the evolving landscape of TCEs targeting PSMA, STEAP1, and DLL3 in PCa. We critically evaluate emerging clinical evidence, arguing that realizing the significant therapeutic potential of TCEs requires overcoming key challenges, including cytokine release syndrome (CRS), limited response durability, and antigen escape. We contend that future success hinges on sophisticated engineering strategies (e.g., affinity tuning, masking, multispecific constructs) and rationally designed combination therapies tailored to disease-specific hurdles. Strategies for toxicity mitigation, the crucial role of biomarker-driven patient selection, and potential integration with existing treatments are also discussed. Accumulating evidence supports TCEs becoming a new therapeutic pillar for advanced PCa, but achieving this demands sustained innovation focused on optimizing efficacy and safety. This review critically connects molecular engineering advancements with clinical realities and future imperatives. Full article

(This article belongs to the Special Issue Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition))

► Show Figures

Journal Menu

Journal Browser

Unravelling Cancer Mechanism and Developing Novel Therapeutics: An Urgent Need to Treat Cancer (2nd Edition)

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI