Hydroxychloroquine (HCQ) is a decades-old oral medication, primarily used for malaria prevention and treatment, and for managing autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus (SLE). It belongs to the class of 4-aminoquinoline antimalarials. Investigating HCQ as a potential anti-cancer agent is a form of drug repurposing, utilizing its known pharmacology against malignant cells. Research suggests HCQ can interfere with cellular processes that cancer cells exploit for survival and growth.
The Biological Rationale: How HCQ Interacts with Cancer Cells
The primary interest in Hydroxychloroquine as an anti-cancer drug stems from its ability to disrupt a cellular recycling process called autophagy. Autophagy, meaning “self-eating,” is a survival mechanism where a cell breaks down damaged components and non-essential proteins to generate energy and building blocks when under stress, such as nutrient deprivation or chemotherapy. Cancer cells often activate this protective process to survive the harsh tumor microenvironment and resist standard treatments.
HCQ is a lysosomotropic agent that easily crosses the lysosome membrane, the cell’s waste disposal compartment, and accumulates there. This accumulation raises the lysosome’s internal pH, neutralizing its acidic environment. Since the digestive enzymes within the lysosome require this acidity to function, the pH increase severely impairs lysosomal activity.
This disruption prevents the final step of autophagy: the fusion of the autophagosome (the sac containing cellular debris) with the lysosome for degradation. By blocking this fusion, HCQ causes undigested material to accumulate within the cancer cell, known as autophagic vacuole formation. This cellular buildup is thought to push the stressed cancer cell past its breaking point, leading to programmed cell death and enhancing concurrent therapies. HCQ has also been shown to affect other pathways, including the Toll-like receptor 9 (TLR9) pathway.
Current Status of Clinical Investigation
In clinical oncology, HCQ is rarely studied as a standalone treatment because its direct anti-cancer effect is considered negligible. Instead, it is investigated as an adjuvant agent, used in combination with standard treatments like chemotherapy, radiation, or targeted therapies. The goal is to sensitize cancer cells to these established treatments by inhibiting their protective autophagic response.
Clinical trials primarily focus on Phase I and Phase II studies, aiming to determine the safety, optimal dosing, and preliminary efficacy of combination regimens. Tumors selected for these trials often rely heavily on autophagy for survival, including aggressive cancers such as melanoma, pancreatic cancer, and glioblastoma.
Early results suggest that HCQ may contribute to improved outcomes in certain cancers, such as glioblastoma and non-Hodgkin lymphoma, when added to standard therapy. However, some studies note that the doses of HCQ tolerated by patients may not consistently achieve the necessary level of autophagy inhibition within the tumor cells. Researchers are actively exploring combination strategies, such as pairing HCQ with immunotherapies like nivolumab for melanoma, or with targeted agents for breast or colorectal cancer, to find the most effective therapeutic windows.
Safety Profile and Considerations in Oncology
Hydroxychloroquine is generally well-tolerated at doses used for autoimmune diseases, but the doses required for a therapeutic effect in cancer trials are often higher. This higher dosing regimen increases the risk of serious adverse effects in cancer patients, who are already vulnerable due to their underlying disease and concurrent treatments.
One significant long-term risk is ocular toxicity, specifically irreversible retinopathy, caused by the drug’s accumulation in retinal pigment epithelial cells. This risk is associated with prolonged use and high cumulative doses, requiring regular ophthalmological exams to detect early changes. Cardiac toxicity is also a concern, as HCQ can interfere with ion channels in the heart, leading to a prolonged QT interval on an electrocardiogram (ECG).
QT prolongation increases the risk of a dangerous irregular heartbeat called Torsades de Pointes. Clinicians must monitor patients for pre-existing cardiac risk factors and drug-drug interactions, as many chemotherapies and other medications given to cancer patients also affect heart rhythm. Gastrointestinal issues like nausea and diarrhea are common side effects, but careful patient selection and monitoring are paramount for managing HCQ’s safety profile in oncology.
Future Directions and Therapeutic Potential
Research focuses on refining HCQ use in cancer, moving past its initial broad application as an autophagy inhibitor. A primary goal is identifying specific biomarkers that predict which patients and tumor types will benefit most. This precision approach spares non-responders from unnecessary drug exposure and focuses therapy on tumors genuinely dependent on autophagy.
Investigators are exploring different dosing schedules, such as intermittent high-dose administration versus continuous lower dosing, to maximize tumor-site drug concentration while minimizing systemic toxicity. New clinical trials evaluate novel drug combinations, pairing HCQ with agents that target different cancer cell vulnerabilities, such as mTOR pathway inhibitors or immune checkpoint blockers. HCQ’s therapeutic potential lies in its established safety profile and low cost, but its success depends on developing strategies to target its cellular effects with greater specificity.