A Combination Therapy of Cyclophosphamide and Immunomodulating Agents in Cancer

Cyclophosphamide is a precursor of alkylating nitrogen mustard and was initially claimed to have antineoplastic and immunosuppressive properties. However, the role of cyclophosphamide as an immune activator has also been reported, depending on the dosage used. The application of lower-dose cyclophosphamide has emerged as a potential approach to cancer treatment. Cyclophosphamide selectively depletes regulatory T cells (Tregs), which dampens the immunological response, thereby rebalancing the immune system to allow other immune cells to act more efficiently. Cyclophosphamide can be either a friend or a foe in cancer treatment, depending on the therapeutic regime. The following questions remain to be answered: Can the cyclophosphamide be used in the presence of other agents? Is there any single immunotherapeutic agent that acts synergistically with cyclophosphamide to effectively alter the immunosuppressive tumor microenvironment? This review emphasizes the role of cyclophosphamide as an immune modulator, both alone and in combination with other immunotherapeutic agents, for effective cancer treatment in preclinical and clinical settings.