Regulatory Mechanisms of Co-Inhibitory Receptors in Tuberculosis Immunity: Implications for Therapeutic Targets

Huicong Liu,1,* Haoran Li,1,* Shanshan Li,1 Yuanyuan Shang,1 Shenjie Tang,2 Yu Pang1 1Department of Bacteriology and Immunology, Beijing Key Laboratory for Key Technologies in Tuberculosis Prevention and Control, Capital Medical University, Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 2Clinical Center on Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shenjie Tang, Clinical Center on Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People’s Republic of China, Email [email protected] Yu Pang, Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People’s Republic of China, Email [email protected]: Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Despite significant advancements in anti-tuberculosis treatment strategies in recent years, TB remains a major infectious disease threat worldwide. Chronic Mtb infection drives T cell exhaustion—characterized by upregulated co-inhibitory receptors—which correlates with TB chronicity, treatment failure, and relapse. Immune checkpoint inhibitors (ICIs) targeting co-inhibitory receptors have achieved groundbreaking progress in the treatment of various malignancies. However, their application in the field of tuberculosis remains controversial. This study provides a comprehensive analysis of TB disease assessment and treatment from the perspective of T cell exhaustion. We investigate the correlation between co-inhibitory receptor expression levels and both disease activity and progression. Furthermore, we analyze the dual impact of targeting these receptors on anti-TB immunity: While blockade of co-inhibitory receptors in T cell exhaustion states restores anti-tuberculosis immunity, excessive inhibition—particularly in hyperimmune conditions—induces detrimental hyperinflammation, exacerbating tissue damage and disrupting immune homeostasis, ultimately worsening clinical outcomes. To address this duality, we emphasize the necessity of personalized immunotherapy strategies based on individual immune profiling, alongside developing novel co-inhibitory receptor blockers and immune modulatory vaccines. This review presents a novel perspective on the application of targeting co-inhibitory receptors in tuberculosis treatment, which will advance the development and application of immunotherapy.Keywords: tuberculosis, co-inhibitory receptors, T cell exhaustion, therapeutic targets