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22 pages, 13140 KiB

Open AccessArticle

Development and Characterization of Optimized Drug-Loaded Niosomes for Delivery of 5-FU and Irinotecan

by Kafilat O. Agbaje, Simeon K. Adesina and Amusa S. Adebayo

Pharmaceutics 2025, 17(7), 900; https://doi.org/10.3390/pharmaceutics17070900 - 11 Jul 2025

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Abstract

Background/Objectives: 5-Fluorouracil (5-FU) and Irinotecan (IRT) are two of the most used chemotherapeutic agents in CRC treatment. However, achieving treatment goals has been hampered by poor drug delivery to tumor sites and associated toxicity from off-target binding to healthy cells. Though the [...] Read more.

Background/Objectives: 5-Fluorouracil (5-FU) and Irinotecan (IRT) are two of the most used chemotherapeutic agents in CRC treatment. However, achieving treatment goals has been hampered by poor drug delivery to tumor sites and associated toxicity from off-target binding to healthy cells. Though the synergism of 5-FU-IRT has provided incremental improvements in clinical outcomes, the short elimination half-life and off-target binding to healthy cells remain significant challenges. We postulated that nanoencapsulation of a combination of 5-FU and IRT in niosomes would prolong the drugs’ half-lives, while over-encapsulation lyophilized powder in Targit^® oral capsules would passively the CRC microenvironment and avoid extensive systemic distribution. Methods: Ranges of formulation and process variables were input into design of experiment (DOE Fusion One) software, to generate screening experiments. Niosomes were prepared using the thin-film hydration method and characterized by size, the polydispersity index (PDI), morphology and intrastructure, and drug loading. Blank niosomes ranged in size from 215 nm to 257 nm. Results: After loading with the 5-FU-IRT combination, the niosomes averaged 251 ± 2.20 nm with a mean PDI of 0.293 ± 0.01. The surfactant-to-cholesterol ratio significantly influenced the niosome size and the PDI. The hydrophilic 5-FU exhibited superior loading compared to the lipophilic IRT molecules, which probably competed with other lipophilic niosome components in niosomes’ palisade layers. In vitro dissolution in biorelevant media showed delayed release until lower intestinal region (IRT) or colonic region (5-FU). Conclusions: Thus, co-nanoencapsulation of 5-FU/IRT in niosomes, lyophilization, and over-encapsulation of powder in colon-specific capsules could passively target the CRC cells in the colonic microenvironment. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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17 pages, 8009 KiB

Open AccessArticle

Metformin-Sensitized Chemotherapy of Docetaxel Nanoemulsions Based on a Sequential Administration

by Junlei Zhang, Jiapeng Mao, Yilong Hu, Xingze Huang, Jian You and Lihua Luo

Pharmaceutics 2025, 17(7), 812; https://doi.org/10.3390/pharmaceutics17070812 - 23 Jun 2025

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Abstract

Background: Chemotherapy has a broad-spectrum anti-tumor effect and is still the core strategy for cancer treatment. However, the side effects caused by its cytotoxicity, the chemoresistance caused by tumor heterogeneity and abnormal microenvironment seriously restrict the efficacy of chemotherapy. Metformin presents the ability [...] Read more.

Background: Chemotherapy has a broad-spectrum anti-tumor effect and is still the core strategy for cancer treatment. However, the side effects caused by its cytotoxicity, the chemoresistance caused by tumor heterogeneity and abnormal microenvironment seriously restrict the efficacy of chemotherapy. Metformin presents the ability to sensitize chemotherapy by interfering with metabolic processes of tumor cells. However, as a dynamic process, metabolic intervention requires a specific time sequence law to optimize its role. Methods: Different administration sequences were screened by in vitro experiments to determine the optimal sequence of metformin and docetaxel. The anti-tumor effect of administration sequence in vivo was investigated in mouse models. The therapeutic advantages were comprehensively evaluated by tumor size, weight change, and survival rate. The immunofluorescent staining and transcriptome analysis were performed to study the mechanisms of the sequential administration strategy. Results: Compared with the subsequent administration and concurrent administration, pretreatment with metformin exhibited a stronger ability toward cell cycle arrest and tumor inhibition with low-dose docetaxel. Moreover, this pre-administration sequence could enhance the anti-tumor immune responses and prevent postoperative recurrence. Conclusions: The optimized chemotherapy sensitization mediated by metabolic intervention required an appropriate administration sequence, which also strengthened the anti-tumor immune responses. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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22 pages, 3036 KiB

Open AccessArticle

Synthesis and Characterization of Transferrin Receptor-Targeted Peptide Combination SN-38 and Rucaparib Conjugate for the Treatment of Glioblastoma

by Perpetue Bataille Backer and Simeon Kolawole Adesina

Pharmaceutics 2025, 17(6), 732; https://doi.org/10.3390/pharmaceutics17060732 - 2 Jun 2025

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Abstract

Background/Objectives: Glioblastoma represents a particularly aggressive and fatal type of brain tumor. Peptide-drug conjugates, which offer the promise of traversing the blood-brain barrier to selectively accumulate in tumor tissues and precisely target cancer cells, are an active area of research. We present the [...] Read more.

Background/Objectives: Glioblastoma represents a particularly aggressive and fatal type of brain tumor. Peptide-drug conjugates, which offer the promise of traversing the blood-brain barrier to selectively accumulate in tumor tissues and precisely target cancer cells, are an active area of research. We present the synthesis and characterization of the T7 peptide (HAIYPRH) as a targeting ligand for the transferrin receptor, which is highly expressed on both the blood-brain barrier and glioma cells. Methods: Using the T7 peptide, the synthesis, characterization, and biological evaluation of a transferrin receptor-targeted, combination SN-38 and rucaparib peptide drug conjugate (T7-SN-38-rucaparib) are described. Results: The T7 peptide drug conjugate readily cleaved in the presence of exogenous cathepsin B, releasing the active drug payloads. In vitro experiments demonstrated potent cytotoxic effects of the T7 peptide drug conjugate on glioblastoma cells (IC₅₀ = 22.27 nM), with reduced toxicity to non-cancerous HEK 293 cells (IC₅₀ = 115.78 nM), indicating selective toxicity toward cancer cells. Further investigations revealed that blocking transferrin receptors with drug-free T7 peptide significantly reduced the conjugate’s cytotoxicity, an effect that could be reversed by introducing exogenous cathepsin B to the cells. Conclusions: These findings highlight the potential of glioblastoma-targeted delivery of SN-38 and rucaparib based on specific recognition of the transferrin receptor for transport across the blood-brain barrier, offering the prospect of reduced toxicity and selective killing of cancer cells. Additionally, since rucaparib does not cross the blood-brain barrier, this work is significant to facilitate the use of rucaparib for the treatment of brain tumors. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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19 pages, 7450 KiB

Open AccessArticle

Curcumin-Induced Apoptotic Cell Death in Human Glioma Cells Is Enhanced by Clusterin Deficiency

by Pinky Sultana and Jiri Novotny

Pharmaceutics 2025, 17(6), 679; https://doi.org/10.3390/pharmaceutics17060679 - 22 May 2025

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Abstract

Background/Objectives: Glioblastoma is an aggressive brain tumor with limited treatment options and significant resistance to conventional therapies. Methods: In this study, we explored the effects of combining curcumin treatment with clusterin inhibition on cell death in glioma cells. Results: We observed that the [...] Read more.

Background/Objectives: Glioblastoma is an aggressive brain tumor with limited treatment options and significant resistance to conventional therapies. Methods: In this study, we explored the effects of combining curcumin treatment with clusterin inhibition on cell death in glioma cells. Results: We observed that the combination of clusterin silencing and curcumin treatment induces cell death. This combination therapy significantly elevated reactive oxygen species (ROS), triggering oxidative stress, which acted as a key upstream mediator of apoptosis. Elevated ROS levels were found to be associated with caspase activation, suggesting apoptosis as the primary mode of cell death. Furthermore, autophagy was induced as a complementary mechanism, with upregulation of LC3B contributing to the enhanced cytotoxic effects. Conclusions: The synergy between clusterin knockdown-induced senescence and curcumin’s pro-apoptotic and pro-autophagic effects highlights a potential novel therapeutic strategy for gliomas. These findings underscore the potential of this combination therapy in overcoming glioma resistance and improving treatment outcomes through the dual induction of oxidative stress and cell death pathways. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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26 pages, 13470 KiB

Open AccessArticle

Drug Combinations Targeting FAK and MEK Overcomes Tumor Heterogeneity in Glioblastoma

by Muhammad Furqan, Richard J. R. Elliott, Peter W. K. Nagle, John C. Dawson, Roza Masalmeh, Virginia Alvarez Garcia, Alison F. Munro, Camilla Drake, Gillian M. Morrison, Steven M. Pollard, Daniel Ebner, Valerie G. Brunton, Margaret C. Frame and Neil O. Carragher

Pharmaceutics 2025, 17(5), 549; https://doi.org/10.3390/pharmaceutics17050549 - 23 Apr 2025

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Abstract

Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis, largely owing to its heterogeneity and the involvement of multiple intracellular signaling pathways that contribute to drug resistance. While recent advancements in targeted drug combination therapies, such [...] Read more.

Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis, largely owing to its heterogeneity and the involvement of multiple intracellular signaling pathways that contribute to drug resistance. While recent advancements in targeted drug combination therapies, such as dabrafenib and trametinib, show promise for certain GBM subgroups, identifying effective drug combinations across the broader GBM population remains a challenge. Integrin-mediated signaling, particularly through Focal Adhesion Kinase (FAK), plays a pivotal role in GBM pathogenesis and invasion, making it a potential therapeutic target and component of future drug combination strategies. Methods: In this study, we utilized a chemogenomic screening approach to identify synergistic drug combinations that target FAK in glioblastoma. We initially employed a CRISPR-engineered GBM model to assess the effects of FAK depletion and subsequently discovered that combining FAK inhibitors such as VS4718 with MEK inhibitors, particularly trametinib, demonstrated synergistic effects. This potent combination was validated using various 2D and 3D assays, including cell viability/apoptosis assessment, synergistic analysis, cellular imaging, and target engagement assays. This combination also effectively inhibited spheroid growth and invasion across a diverse panel of patient-derived GBM stem cells. Molecular mechanisms underlying these effects include suppression of multiple kinase signaling pathways and enhanced apoptosis, elucidated using Reverse-Phase Protein Array (RPPA) profiling and Western blot validation. Result: In vivo, combination therapy significantly reduced the tumor volume in orthotopic transplantation models. Conclusions: These findings suggest that the combination of FAK and MEK inhibitors represents a promising therapeutic strategy to overcome the challenges of GBM treatment. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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21 pages, 2096 KiB

Open AccessArticle

The Impact of Doxycycline as an Adjunctive Therapy on Prostate-Specific Antigen, Quality of Life, and Cognitive Function in Metastatic Prostate Cancer Patients: A Phase II Randomized Controlled Trial

by José Guzmán-Esquivel, Hossana S. Garcia-Garcia, Gustavo A. Hernández-Fuentes, Jesús Venegas-Ramírez, Carlos D. Barajas-Mejía, Idalia Garza-Veloz, Margarita L. Martinez-Fierro, Nancy E. Magaña-Vergara, José A. Guzmán-Solórzano, Patricia Calvo-Soto, Oscar N. Avila-Zamora, Mercedes Fuentes-Murguia, Gabriel Ceja-Espíritu and Iván Delgado-Enciso

Pharmaceutics 2025, 17(4), 404; https://doi.org/10.3390/pharmaceutics17040404 - 24 Mar 2025

Viewed by 1736

Abstract

Background/Objectives: Metastatic prostate cancer remains a major clinical challenge, with limited therapeutic options. Doxycycline, a tetracycline antibiotic with anti-inflammatory properties, has shown potential as an adjunctive therapy. This study aimed to evaluate its efficacy in reducing prostate-specific antigen (PSA) levels and improving quality [...] Read more.

Background/Objectives: Metastatic prostate cancer remains a major clinical challenge, with limited therapeutic options. Doxycycline, a tetracycline antibiotic with anti-inflammatory properties, has shown potential as an adjunctive therapy. This study aimed to evaluate its efficacy in reducing prostate-specific antigen (PSA) levels and improving quality of life in patients receiving standard treatment for metastatic prostate cancer. Methods: This phase II, double-blind, randomized controlled trial included 45 participants (aged 57–81 years) assigned to doxycycline (100 mg daily) or a placebo for six months. The primary outcome was the percentage change in PSA levels at 3 and 6 months. Secondary outcomes included quality of life (EQ-5D-5L), cognitive function (Mini-Mental State Examination), and glucose levels. Additionally, a structure–activity relationship (SAR) analysis was performed through an extensive bibliographic review to identify pharmacophores responsible for doxycycline’s biological activity, particularly its tetracyclic core. The SAR analysis included tetracyclines and derivatives, androgen-targeting agents, and other pharmacologically relevant molecules used in prostate cancer therapy. Statistical analysis was conducted using multivariate logistic regression. Results: At six months, the doxycycline group showed a median PSA reduction of 60% compared to 10% in the placebo group (p = 0.043). A ≥50% reduction in PSA levels was observed in 71.4% of patients receiving doxycycline versus 20.8% in the placebo group (p = 0.001), with an adjusted relative risk of 10.309 (95% CI: 2.359–45.055, p = 0.002). Quality of life improved, with 7.1% of doxycycline-treated patients reporting poor quality of life compared to 42.9% in the placebo group (p = 0.028). A slight improvement in cognitive function was also noted (p = 0.037). SAR analysis suggested that the tetracyclic ring of doxycycline may play a crucial role in its observed biological effects. Conclusions: Doxycycline demonstrates potential as an adjunctive therapy in metastatic prostate cancer by reducing PSA levels and improving quality of life. The SAR analysis supports the hypothesis that its tetracyclic structure may be responsible for its therapeutic effects. Further large-scale trials are warranted to confirm these findings. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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18 pages, 2199 KiB

Open AccessArticle

The Co-Administration of Paclitaxel with Novel Pyridine and Benzofuran Derivatives that Inhibit Tubulin Polymerisation: A Promising Anticancer Strategy

by Magdalena Perużyńska, Radosław Birger, Patrycja Kłos, Halina Kwiecień, Łukasz Struk, Jacek G. Sośnicki, Laurence Lafanechère and Marek Droździk

Pharmaceutics 2025, 17(2), 223; https://doi.org/10.3390/pharmaceutics17020223 - 9 Feb 2025

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Abstract

Background: Paclitaxel (PTX), a crucial microtubule-stabilising agent in cancer treatment, is limited by its adverse effects and hydrophobic nature, which necessitate the use of toxic solvents. This study proposes a novel approach combining PTX with new microtubule-destabilising compounds at low, safe doses [...] Read more.

Background: Paclitaxel (PTX), a crucial microtubule-stabilising agent in cancer treatment, is limited by its adverse effects and hydrophobic nature, which necessitate the use of toxic solvents. This study proposes a novel approach combining PTX with new microtubule-destabilising compounds at low, safe doses that are ineffective when used individually. Objective: The aim was to evaluate the therapeutic efficacy of combining PTX with previously described pyridine (S1, S22) and benzofuran derivatives (13b, 14), which have demonstrated promising anticancer properties by inhibiting microtubule polymerisation. Methods: The PrestoBlue assay was used to determine the optimal concentrations of each compound, enabling synergistic interactions with a low dose of PTX in HeLa cervical cancer cells. The combined effects of the compounds and PTX on apoptosis, cell cycle distribution, and mitotic spindle formation were then evaluated. Results: The results showed that compounds 13b (1 µM), 14 (0.1 µM), S1 (2 µM), and S22 (2 µM) enhanced the proapoptotic and antimitotic effects of 1 nM PTX, which was ineffective alone. Notably, live-cell imaging revealed that the concurrent use of S1 and PTX produced effects similar to those of a higher PTX concentration (5 nM). Conclusions: These findings suggest that these compounds enhance the anticancer efficacy of low-dose PTX, potentially paving the way for more effective and safer cancer therapies. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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14 pages, 2617 KiB

Open AccessArticle

ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer

by Andrés Barba, Laura López-Vilaró, Malena Ferre, Margarita Majem, Sergio Martinez-Recio, Olga Bell, María J. Arranz, Juliana Salazar and Ivana Sullivan

Pharmaceutics 2024, 16(9), 1121; https://doi.org/10.3390/pharmaceutics16091121 - 25 Aug 2024

Cited by 1 | Viewed by 2271

Abstract

Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and [...] Read more.

Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38–7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09–17.55] months versus negative expression 13.3 [95% CI 7.32–19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade ≥ 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08–9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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Review

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31 pages, 4404 KiB

Open AccessReview

Recent Advances in the Use of Ganoderma lucidum and Coriolus versicolor Mushrooms to Enhance the Anticancer Efficacy of EGFR-Targeted Drugs in Lung Cancer

by Hang Zhang, Longling Wang, Yuet Wa Chan, William C. Cho, Zhong Zuo and Kenneth K. W. To

Pharmaceutics 2025, 17(7), 917; https://doi.org/10.3390/pharmaceutics17070917 (registering DOI) - 15 Jul 2025

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the major subtype, accounting for more than 85% of all lung cancer cases. Recent advances in precision oncology have allowed NSCLC patients bearing specific oncogenic epidermal growth [...] Read more.

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the major subtype, accounting for more than 85% of all lung cancer cases. Recent advances in precision oncology have allowed NSCLC patients bearing specific oncogenic epidermal growth factor receptor (EGFR) mutations to respond well to EGFR tyrosine kinase inhibitors (TKIs). Due to the high EGFR mutation frequency (up to more than 50%) observed particularly in Asian NSCLC patients, EGFR-TKIs have produced unprecedented clinical responses. Depending on their binding interactions with EGFRs, EGFR-TKIs are classified as reversible (first-generation: gefitinib and erlotinib) or irreversible inhibitors (second-generation: afatinib and dacomitinib; third-generation: osimertinib). While the discovery of osimertinib represents a breakthrough in the treatment of NSCLC, most patients eventually relapse and develop drug resistance. Novel strategies to overcome osimertinib resistance are urgently needed. In Asian countries, the concomitant use of Western medicine and traditional Chinese medicine (TCM) is very common. Ganoderma lucidum (Lingzhi) and Coriolus versicolor (Yunzhi) are popular TCMs that are widely consumed by cancer patients to enhance anticancer efficacy and alleviate the side effects associated with cancer therapy. The bioactive polysaccharides and triterpenes in these medicinal mushrooms are believed to contribute to their anticancer and immunomodulating effects. This review presents the latest update on the beneficial combination of Lingzhi/Yunzhi and EGFR-TKIs to overcome drug resistance. The effects of Lingzhi/Yunzhi on various oncogenic signaling pathways and anticancer immunity, as well as their potential to overcome EGFR-TKI resistance, are highlighted. The potential risk of herb–drug interactions could become critical when cancer patients take Lingzhi/Yunzhi as adjuvants during cancer therapy. The involvement of drug transporters and cytochrome P450 enzymes in these herb–drug interactions is summarized. Finally, we also discuss the opportunities and future prospects regarding the combined use of Lingzhi/Yunzhi and EGFR-TKIs in cancer patients. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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28 pages, 626 KiB

Open AccessReview

Metformin-Based Combination Approaches for Triple-Negative Breast Cancer

by Zaid Sirhan, Aya Abu Nada, Nadeen Anabtawi, Anita Thyagarajan and Ravi P. Sahu

Pharmaceutics 2025, 17(5), 558; https://doi.org/10.3390/pharmaceutics17050558 - 24 Apr 2025

Cited by 1 | Viewed by 905

Abstract

Numerous anti-diabetic medications, including metformin, have been explored for their anticancer effects because of the substantial correlation between diabetes and cancer incidence. Metformin has recently gained interest for its anticancer effects against malignancies such as breast cancer, one of the leading causes of [...] Read more.

Numerous anti-diabetic medications, including metformin, have been explored for their anticancer effects because of the substantial correlation between diabetes and cancer incidence. Metformin has recently gained interest for its anticancer effects against malignancies such as breast cancer, one of the leading causes of death among women worldwide. The cancer-related characteristics of cell proliferation, invasion, migration, and apoptosis are all targeted by metformin. Among breast cancer patients, triple-negative breast cancer (TNBC) is linked to an increased risk of early recurrence and metastases and has poor prognosis. In addition, TNBC has fewer treatment options compared to other breast cancer subtypes because it lacks hormone receptors and human epidermal growth factor receptor 2 (HER2), and it often develops resistance to available treatment options. The current review highlights the recent updates on the mechanistic insights and the efficacy of metformin and metformin-based approaches for the treatment of TNBC. We logically discuss the experimental evidence from the in vitro and in vivo studies exploring metformin’s effects on metabolic pathways, and then its combination with other therapeutic agents, targeting cell signaling pathways, and approaches to enhance metformin’s effects. We also present clinical studies that underscore the beneficial outcomes of metformin or its combination with other agents in TNBC patients. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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17 pages, 2217 KiB

Open AccessReview

Targeting DLL3: Innovative Strategies for Tumor Treatment

by Hui Wang, Tong Zheng, Dan Xu, Chao Sun, Daqing Huang and Xiongxiong Liu

Pharmaceutics 2025, 17(4), 520; https://doi.org/10.3390/pharmaceutics17040520 - 16 Apr 2025

Viewed by 1143

Abstract

Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with [...] Read more.

Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with therapies targeting DLL3 for cancer treatment. The biological characteristics of DLL3 and its role in the Notch signaling pathway are introduced first, delving into the role of DLL3 in tumorigenesis and cancer progression. Next, current therapeutic approaches targeting DLL3 are described, including antibody–drug conjugates, T cell engagers, chimeric antigen receptor T cells, and radiopharmaceutical therapy, highlighting their effectiveness and safety in clinical trials. Despite the promising prospects, difficulties remain in the use of DLL3 as a therapeutic target due to tumor heterogeneity, the development of resistance, potential adverse effects, and barriers to patient stratification. Therefore, the potential of combination therapies, the use of innovative drug delivery systems, and ongoing clinical trial advancements are also discussed. Finally, the potential of DLL3-targeted therapies is summarized, highlighting the importance of multidisciplinary research to guide the clinical application and optimization of this emerging treatment strategy. These approaches might provide new therapeutic options, potentially starting a new era in cancer treatment. Full article

(This article belongs to the Special Issue Combination Therapy Approaches for Cancer Treatment)

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