The emerging role of co-stimulatory molecules and their agonistic mAb-based combination therapies in melanoma
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Updated: Dec 4, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Shan He1, Jinhua Xu1, Jinfeng Wu1
1Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, PR China.
Abstract:
Although anti-PD-1/L1 and anti-CTLA-4 antibodies, the validated immune checkpoint blockades, can elicit durable long-lasting antitumor immunity and improve the clinical outcomes of melanoma treatment, there are still a fraction of patients who did not receive therapeutic benefits as expected. In addition to findings of blocking the co-inhibitory pathways, the preclinical and clinical evidence suggests that triggering the co-stimulatory pathways through agonists such as CD137, OX40, CD40, GITR and CD27 may be a rational next step for melanoma therapy. In this review, we discuss the progress of studies on these co-stimulatory molecules in terms of their promising therapeutic effects and underlying antitumor mechanisms, and provide a review of the possible combinations that orchestrate the interplay of co-stimulatory agonistic mAbs and other therapies for treating melanoma, including inhibitory immune checkpoint mAbs, adoptive T cell therapy, chemotherapy and radiotherapy. We also briefly present the limitations and challenges involved in these co-stimulatory agonistic mAb-based combination strategies for melanoma patients.
Insights
Melanoma patients may benefit from new immune therapies that activate co-stimulatory pathways, complementing current checkpoint blockade treatments. This approach explores novel combinations for enhanced antitumor immunity.
Area of Science:
- Immunology
- Oncology
- Cancer Therapy
Background:
- Immune checkpoint inhibitors (ICIs) like anti-PD-1/L1 and anti-CTLA-4 antibodies have improved melanoma treatment outcomes.
- However, a significant portion of patients do not respond adequately to current ICI therapies.
Purpose of the Study:
- To review the therapeutic potential of co-stimulatory pathway agonists in melanoma treatment.
- To explore combination strategies involving co-stimulatory agonists and other melanoma therapies.
Main Methods:
- Literature review of preclinical and clinical studies on co-stimulatory molecules (CD137, OX40, CD40, GITR, CD27).
- Analysis of antitumor mechanisms and therapeutic effects of co-stimulatory agonists.
- Evaluation of combination strategies with ICIs, adoptive T cell therapy, chemotherapy, and radiotherapy.
Main Results:
- Co-stimulatory pathway agonists show promising therapeutic effects and antitumor mechanisms in melanoma.
- Combination strategies involving co-stimulatory agonists offer potential for enhanced efficacy.
- Challenges and limitations of these novel combination strategies are identified.
Conclusions:
- Activating co-stimulatory pathways represents a rational next step for improving melanoma immunotherapy.
- Combination therapies integrating co-stimulatory agonists hold significant promise for overcoming resistance to current treatments.
- Further research is needed to address the challenges associated with co-stimulatory agonistic mAb-based combination strategies.
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