Leishmaniasis: pathogenesis, host immunity, and the evolving landscape of immunotherapy and immunochemotherapy

Leishmaniasis is a group of neglected tropical diseases caused by protozoan parasites of the genus Leishmania, transmitted by the bite of infected female phlebotomine sandflies. Manifesting as cutaneous (CL), mucocutaneous (MCL), and visceral (VL) forms, it remains a major global health burden, affecting millions in tropical and subtropical regions, with an estimated 30,000 new VL cases annually and over 1 billion people at risk. The disease is defined not only by the parasite but by the host immune response: protective Th1-mediated cellular immunity, characterized by IFN-γ, TNF-α, IL-12, and nitric oxide production, is essential for parasite clearance, while Th2 skewing, IL-10 dominance, and immune anergy permit progressive disease. Current chemotherapy relies on a limited and problematic drug arsenal. Pentavalent antimonials face widespread resistance, particularly in the Indian subcontinent. Amphotericin B achieves high cure rates but demands hospitalization and causes significant nephrotoxicity. Miltefosine, the only oral agent available, achieves 94-97% initial cure rates in Indian VL (Bihar region) but is complicated by teratogenicity, gastrointestinal toxicity, 10-20% relapse rates, and emerging resistance. No licensed vaccine exists for human leishmaniasis. This narrative review synthesizes current understanding of Leishmania pathogenesis and host immunity, evaluates the treatment landscape across drug classes, and critically examines immunotherapy and immunochemotherapy strategies, including cytokine-based approaches, TLR agonists, therapeutic vaccines, and novel platforms such as α-Gal epitope-targeted virus-like particles (VLPs), as strategies to restore protective immunity and address the limitations of chemotherapy alone. We also assess mucosal vaccination as an underexplored delivery route with documented advantages for Th1 polarization and tissue-resident memory induction. Together, these approaches point toward a future of combination immunochemotherapy capable of achieving durable cure, preventing relapse and post-kala-azar dermal leishmaniasis (PKDL), and overcoming drug resistance across clinical forms of leishmaniasis.