Hydroxychloroquine as Adjuvant Therapy with Immunotherapy for Prevention of Activation of Latent Tuberculosis: Restoring Interferon-Gamma Competence in Patients Receiving TNF-Alpha Inhibitors

Background: Tumor necrosis factor-alpha (TNF-α) inhibitors have transformed the management of chronic inflammatory diseases, yet they impose a substantially elevated risk of tuberculosis (TB) reactivation—up to 25-fold depending on the agent used. This risk is principally driven by disruption of granuloma architecture and suppression of interferon-gamma (IFN-γ)–dependent macrophage bactericidal activity. Current prophylactic strategies rely predominantly on isoniazid chemoprophylaxis, which carries hepatotoxicity risks and compliance challenges. There remains an unmet need for adjunctive immunomodulatory approaches that can selectively bolster anti-mycobacterial immunity without exacerbating the underlying autoimmune condition. Hypothesis: We propose that low-dose hydroxychloroquine (HCQ), administered concomitantly with TNF-α inhibitor therapy, can serve as a targeted immunomodulatory prophylactic strategy against TB reactivation. This hypothesis is grounded in recent single-cell transcriptomic evidence demonstrating that HCQ selectively upregulates IFNG expression and cytotoxicity-associated gene programs (GZMA, GZMB, PRF1, NKG7) in effector CD8+ T cells while simultaneously reducing the dysfunctional CD38+ CD8+ T cell subset. We posit that this CD8+ T cell–mediated IFN-γ augmentation can partially compensate for the TNF-α inhibitor–induced deficit in the IL-12/IFN-γ axis, thereby preserving granuloma integrity and macrophage mycobactericidal function. Evidence Synthesis: We integrate mechanistic data from immunology, pharmacology, and TB pathogenesis to construct a multi-layered rationale. We examine the dose-dependent immunomodulatory effects of HCQ, the differential impact of TNF-α inhibitors on mycobacterial immunity, and the critical role of IFN-γ in phagosome maturation and granuloma maintenance.Conclusion: This hypothesis establishes a mechanistically grounded framework for repurposing HCQ as adjunctive TB prophylaxis in the anti-TNF setting. We propose a phased translational research program to evaluate this novel immunomodulatory strategy.