When the host is not healthy: Rethinking tuberculosis drug targets in comorbid conditions.

Tuberculosis (TB) frequently coexists with chronic conditions such as diabetes, HIV, malnutrition, sarcoidosis, and lung cancer. These comorbidities profoundly reshape the host immune, metabolic, and tissue environments, disrupting pathways that govern Mycobacterium tuberculosis (Mtb) containment and altering responses to both antimicrobial and host-directed therapies. Yet, most TB drug discovery pipelines continue to rely on "healthy-host" experimental models, overlooking the biological heterogeneity of the populations most affected by the disease. In this review, we argue that TB should be reframed not as a single disease entity, but as a spectrum of comorbidity-modulated disease mechanisms shaped by host health status. We synthesize mechanistic evidence demonstrating how comorbidities rewire macrophage function, immune signaling, metabolic programs, autophagy, granuloma architecture, and drug distribution and accessibility, with direct consequences for pharmacokinetics, pharmacodynamics, and treatment efficacy. Using the framework of "One Drug, Multiple Disease Mechanisms," we highlight opportunities to repurpose drugs developed for comorbid conditions-such as metabolic, cardiovascular, neuropsychiatric, and oncologic agents-as cross-cutting host-directed interventions in TB. We further discuss emerging experimental and computational strategies, including comorbidity-mimicking cellular systems, organoids, CRISPR-based screens, dual-disease animal models, and network-level and systems-biology pathway modeling, to embed host complexity into TB target discovery and validation. By embracing host heterogeneity rather than filtering it out, TB research can prioritize resilient and translationally robust targets and advance therapeutic strategies that are effective across diverse, comorbidity-burdened patient populations.