Key Biomarkers and Immunotherapy Advances in Cancer Treatment

Role of DLX4 in Cancer Progression and Immune Infiltration

Distal-less homeobox 4 (DLX4) has emerged as a crucial biomarker in the study of cancer, particularly due to its association with various malignancies, including breast and renal cancers. Recent multi-omics analyses have demonstrated that DLX4 is not only overexpressed in several cancer types but is also associated with poor prognosis and immune infiltration levels (Kou et al., 2025). In a comprehensive analysis, DLX4 was found to be upregulated in 26 different cancers, indicating its potential role as a universal cancer biomarker (Kou et al., 2025).

The mechanisms through which DLX4 influences cancer progression are multifaceted. It promotes tumor cell proliferation by regulating cell cycle proteins such as cyclin D1 and c-Myc, while also inhibiting apoptosis via the upregulation of anti-apoptotic factors like Bcl-2 (Kou et al., 2025). Moreover, DLX4 facilitates tumor invasiveness through the modulation of matrix metalloproteinases (MMPs) and the epithelial-mesenchymal transition (EMT) process, which is critical for cancer cell migration and metastasis (Kou et al., 2025).

Importantly, the expression of DLX4 correlates with tumor mutational burden and immune scores, suggesting that it plays a significant role in shaping the tumor microenvironment (Kou et al., 2025). In renal clear cell carcinoma, for instance, elevated DLX4 expression has been linked to the infiltration of regulatory T cells (Tregs), which are known to suppress anti-tumor immunity (Kou et al., 2025). This immune evasion mechanism highlights the importance of DLX4 not only as a biomarker but also as a potential therapeutic target in immunotherapy strategies.

Multi-Omics Analysis of Breast Cancer and Prognostic Factors

Multi-omics approaches have revolutionized our understanding of breast cancer by integrating genomic, transcriptomic, and proteomic data to reveal complex biological interactions. In a recent study focusing on key biomarkers such as Cyclin B1 (CCNB1), Polo-Like Kinase 1 (PLK1), and Heparanase (HPSE), researchers demonstrated how these proteins significantly influence breast cancer progression and patient prognosis (Su et al., 2025).

The study revealed that CCNB1 and PLK1 are upregulated in breast cancer tissues compared to normal tissues, correlating with increased tumor proliferation and metastasis (Su et al., 2025). Furthermore, high expression levels of these proteins were associated with worse overall survival outcomes, particularly in patients harboring TP53 mutations, which are common in aggressive breast cancers (Su et al., 2025). Enrichment analyses indicated that CCNB1 and PLK1 activate critical signaling pathways associated with cell cycle regulation and tumorigenesis, underscoring their potential as therapeutic targets (Su et al., 2025).

HPSE, on the other hand, was found to modulate immune responses within the tumor microenvironment, suggesting that its expression levels could influence the efficacy of immunotherapies (Su et al., 2025). The integration of data from transcriptomics, proteomics, and methylation profiling provided a comprehensive view of the tumor landscape, identifying potential prognostic factors that could guide personalized treatment strategies.

Impact of Antibody-Drug Conjugates on Gastric Cancer Therapy

Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic approach in gastric cancer (GC), especially for patients who have limited options following conventional treatments. ADCs combine the targeting capabilities of monoclonal antibodies with the cytotoxic effects of chemotherapeutic agents, allowing for selective delivery to cancer cells while minimizing systemic toxicity (Yin et al., 2025).

Recent clinical trials have highlighted the efficacy of ADCs such as trastuzumab deruxtecan (DS-8201a) and RC48 in HER2-positive gastric cancer. For instance, DS-8201a has shown encouraging results with an objective response rate (ORR) of 23.6% and a median progression-free survival (PFS) of 4.1 months in advanced GC patients previously treated with trastuzumab (Yin et al., 2025). The mechanism of action involves binding to HER2 receptors on tumor cells, leading to internalization and subsequent release of cytotoxic payloads, resulting in cell death.

Despite the significant advancements, challenges remain, including the management of adverse effects and the potential for developing resistance to ADCs. Ongoing research aims to optimize linker technology and payload selection to enhance the therapeutic index of ADCs in GC (Yin et al., 2025). The future of gastric cancer treatment will likely involve a combination of ADCs with immunotherapies to improve outcomes further.

Mechanisms of Resistance in Cancer Treatments and Solutions

Resistance to cancer therapies, particularly in the context of targeted treatments like ADCs and immunotherapies, presents a significant challenge in oncology. Various mechanisms contribute to both primary and acquired resistance, complicating treatment regimens and leading to suboptimal patient outcomes (Yin et al., 2025).

One major mechanism involves the downregulation of target antigens, which can occur through genetic mutations or changes in the tumor microenvironment (Yin et al., 2025). For example, HER2-positive tumors may lose HER2 expression following treatment with HER2-targeted therapies, leading to reduced efficacy of subsequent treatments (Yin et al., 2025). Additionally, the upregulation of drug efflux pumps and alterations in intracellular signaling pathways can also facilitate resistance by preventing therapeutic agents from exerting their effects (Yin et al., 2025).

To address these challenges, researchers are exploring combination therapies that integrate ADCs with immune checkpoint inhibitors (ICIs) or other targeted therapies. This strategy aims to enhance the overall therapeutic efficacy while mitigating the development of resistance (Yin et al., 2025). Understanding the molecular basis of resistance through genomic and transcriptomic analyses will be crucial for developing novel strategies to overcome these barriers and improve treatment outcomes.

Future Directions for Targeting Fusion Genes in Cancer Therapy

Fusion genes represent a hallmark of various cancers, resulting from chromosomal rearrangements that can drive tumorigenesis. Targeting these fusion genes with specific inhibitors has shown promise in improving treatment outcomes for patients with specific genetic alterations (Uusi-Mäkelä et al., 2024).

Recent advancements have highlighted the importance of understanding the mechanisms underlying fusion gene formation and their functional consequences in cancer. For instance, the BCR::ABL1 fusion gene, commonly associated with chronic myeloid leukemia (CML), has led to the development of targeted therapies that have dramatically improved patient survival rates (Uusi-Mäkelä et al., 2024). Similarly, other fusion genes such as EML4::ALK and NTRK fusions have generated interest as therapeutic targets in lung cancer and other malignancies.

The creation of databases like FusionPub aims to compile and analyze data from clinical trials and research studies that focus on fusion genes and their interactions with therapeutic agents. By integrating information on drug interactions, patient responses, and clinical outcomes, such platforms can facilitate the discovery of novel therapeutic strategies and help clinicians make informed decisions regarding treatment options (Uusi-Mäkelä et al., 2024).

Table 1: Summary of Key Fusion Genes and Their Associated Drugs

FAQ

What are the key biomarkers in cancer treatment? Key biomarkers include DLX4, CCNB1, PLK1, and HPSE, which are associated with cancer progression and prognosis.

How do antibody-drug conjugates work? ADCs combine monoclonal antibodies with cytotoxic drugs, targeting specific cancer cells to deliver the drug directly, minimizing harm to normal tissues.

What challenges are associated with cancer immunotherapy? Challenges include resistance mechanisms, adverse effects, and the need for reliable biomarkers to predict treatment responses.

What is the significance of fusion genes in cancer? Fusion genes result from chromosomal rearrangements, leading to the production of fusion proteins that can drive cancer progression and serve as therapeutic targets.

How can research on fusion genes improve cancer treatment? By understanding the specific mechanisms and pathways involved, researchers can develop targeted therapies that are more effective and personalized for patients.

References

1. Kou, Z., Zhu, S., Zhu, J., Wang, S., Zheng, Y., Zhou, S., Si, Z., & Zhu, H. (2025). Multi-omics analysis identifies DLX4 as a novel biomarker for diagnosis, prognosis, and immune infiltration: from pan-cancer to renal cancer. Discover Oncology, 2730-6011. https://doi.org/10.1007/s12672-025-02258-z

2. Su, Q., Fang, L., Li, C., Yue, L., Yun, Z., Zhang, H., Liu, Q., Ma, R., Zhong, P., Liu, H., Lou, Z., Zhang, R., Chen, Z., & Tan, Y. (2025). Multi-omics insights into the roles of CCNB1, PLK1, and HPSE in breast cancer progression: implications for prognosis and immunotherapy. Discover Oncology, 2730-6011. https://doi.org/10.1007/s12672-025-02282-z

3. Yin, Q., Zhang, Y., Xie, X., Hou, M., & Chen, X. (2025). Navigating the future of gastric cancer treatment: a review on the impact of antibody-drug conjugates. Cell Death Discovery, 2058-7716. https://doi.org/10.1038/s41420-025-02429-5

4. Uusi-Mäkelä, M., Harjula, S.-K. E., Junno, M., Sillanpää, A., Nätkin, R., Niskanen, M. T., & Sara. (2024). The inflammasome adaptor pycard is essential for immunity against Mycobacterium marinum infection in adult zebrafish. Disease Models & Mechanisms, 1754-8403