Combining Repurposed Drugs with Immunotherapy: A Novel Approach to Cancer Treatment (2025)

By Editorial Team - May 06, 2025

Introduction

Cancer remains a leading cause of morbidity and mortality worldwide, with many patients facing limited options beyond conventional therapies such as chemotherapy, radiotherapy, and molecularly targeted agents36. While immunotherapy-particularly immune checkpoint inhibitors (ICIs)-has revolutionized the treatment landscape for several malignancies, its efficacy is often hampered by intrinsic and acquired resistance, as well as by the immunosuppressive tumor microenvironment (TME)2 67. Consequently, there is an urgent need for innovative strategies that can enhance immunotherapeutic effectiveness and broaden its clinical applicability.

Drug repurposing, the process of identifying new therapeutic uses for existing medications, has emerged as a promising and cost-effective approach to accelerate the development of novel cancer treatments1 2 56. Repurposed drugs offer well-characterized safety profiles and pharmacokinetics, enabling rapid clinical translation. Recent research has highlighted the potential of various non-oncology drugs-including antidiabetics, antihypertensives, antifungals, and antiparasitics-to modulate the immune response, alter the TME, and synergize with immunotherapy2 4 67. This combination strategy may overcome resistance to ICIs, enhance antitumor immunity, and improve outcomes for patients with refractory or aggressive cancers.

This review provides an updated synthesis of the mechanisms, clinical evidence, and future directions for the integration of repurposed drugs with immunotherapy, with a special focus on the emerging combination of ivermectin and balstilimab in metastatic triple-negative breast cancer (mTNBC).

Diverse cancer hallmarks targeted by repurposed non-oncology drugs. This figure was created with Biorender.com. Source: Nature 2024

Combination of Repurposed Drugs and Immunotherapy in Cancer Treatment

Mechanisms of Synergy

Repurposed drugs enhance immunotherapy efficacy through several key mechanisms:

Tumor Microenvironment (TME) Modulation: Agents such as metformin and antihypertensives can increase CD8+ T-cell infiltration, reduce regulatory T cells (Tregs), and repolarize tumor-associated macrophages, thereby reversing the immunosuppressive TME and supporting immune-mediated tumor destruction2 67.
Overcoming Immune Checkpoint Inhibitor Resistance: DNA hypomethylating agents (e.g., guadecitabine) can restore ICI sensitivity by reversing epigenetic silencing of immune-related genes36.
Induction of Immunogenic Cell Death: Drugs like disulfiram and antifungals promote immunogenic cell death and enhance antigen presentation, making tumors more susceptible to immune attack67.

Key Drug Classes and Examples

Antidiabetics (e.g., Metformin): Modulate immune populations, increase CD8+ T-cell activity, and improve dendritic cell function2 67.
Antihypertensives: Enhance immune cell infiltration and reduce angiogenesis, supporting antitumor immunity67.
Antifungals: Repolarize macrophages and support antitumor immune responses6.
Disulfiram (DSF): Induces immunogenic cell death and upregulates PD-L1, enhancing ICI response in various cancers6.
Ivermectin and Balstilimab in mTNBC: Ivermectin, an antiparasitic drug, induces immunogenic cell death, disrupts cancer stem cell populations, and transforms “cold” tumors into “hot” by promoting T-cell infiltration. Balstilimab, an anti-PD-1 antibody, releases the brakes on T-cell immunity. Their combination is under clinical investigation (NCT05318469) for mTNBC, aiming to overcome immune resistance and improve outcomes in this aggressive cancer subtype26.

Landmark Breakthrough: Dostarlimab Achieves 100% Remission in dMMR Rectal Cancer

A landmark phase II clinical trial at Memorial Sloan Kettering Cancer Center (MSK) evaluated dostarlimab (Jemperli), a PD-1 inhibitor, in patients with locally advanced mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) rectal cancer. The trial enrolled 42 patients with stage II or III dMMR tumors, administering dostarlimab monotherapy every three weeks for six months.

Expanding Horizons: Potential Synergy between Immunotherapy and Repurposed Drugs

MSK investigators are exploring this immunotherapy-first approach in other dMMR cancers, including gastric, prostate, and pancreatic tumors. This success story underscores the potential synergy between immunotherapy and repurposed drugs that modulate the TME to extend benefits beyond dMMR tumors.

Clinical Outcomes and Future Directions

Early clinical and preclinical studies indicate that combining repurposed drugs with immunotherapy can restore ICI sensitivity, enhance antitumor immune responses, and improve outcomes in hard-to-treat cancers2 3 67. Systematic approaches-including high-throughput screening and computational modeling-are being employed to identify optimal drug-immunotherapy combinations6. Ongoing clinical trials, such as those evaluating ivermectin and balstilimab in mTNBC (metastatic triple negative breast cancer), will clarify their potential to transform the management of aggressive malignancies.

The dostarlimab trial’s success provides a compelling clinical benchmark and proof-of-concept for immunotherapy monotherapy in select populations. Integrating repurposed drugs that prime the immune system or reverse resistance mechanisms may broaden these benefits to more cancer types and patients.

Conclusion

Repurposed drugs combined with immunotherapy represent a transformative strategy in oncology, offering hope for improved outcomes, reduced toxicity, and personalized treatment. Landmark clinical successes, including the 100% remission rate with dostarlimab in dMMR (deficient mismatch repair) rectal cancer, demonstrate the power of precision immunotherapy. Continued research and clinical validation will be critical to fully realize the potential of these combination approaches.

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