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**Cyclophosphamide + hydroxychloroquine** is a combination regimen consisting of two long-established small-molecule drugs: cyclophosphamide, an alkylating chemotherapy agent, and hydroxychloroquine, an antimalarial and immunomodulatory drug. Cyclophosphamide works by covalently binding to DNA, causing DNA cross-linking and inhibiting DNA replication, which leads to cell death in rapidly dividing cells. Hydroxychloroquine acts as a lysosomotropic agent that accumulates in lysosomes, raising vacuolar pH and inhibiting autophagy, while also binding to nucleic acids to prevent the activation of endosomal Toll-like receptors (TLR7 and TLR9). This combination has been investigated in academic and investigator-sponsored clinical trials, notably for the treatment of refractory multiple myeloma (as part of a multi-drug regimen) and severe thrombocytopenia in systemic lupus erythematosus (SLE). Additionally, preclinical research suggests that hydroxychloroquine may protect against cyclophosphamide-induced premature ovarian failure by reducing granulosa cell senescence and modulating the mtDNA-cGAS signaling pathway.
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