Nanotechnology-based shikonin delivery strategies for modulating the tumor immune microenvironment efficacy.

Malignant tumors remain a major cause of global mortality and pose a formidable threat to human health. While natural and synthetic substances have been explored for cancer therapy, natural products such as shikonin (SHK), a naphthalene quinone extracted from Lithospermum erythrorhizon, offer unique advantages due to their plant-based origins and multifaceted pharmaceutical properties. SHK exhibits potent anticancer activity and inhibits pyruvate kinase M2 (PKM2), which suppresses glycolysis and lactate metabolism. The metabolic regulation inhibits adenosine triphosphate (ATP) production and suppresses the immunosuppressive phenotype of immune cells (e.g., Tregs), thus remodeling the tumor immune microenvironment. Additionally, SHK promotes apoptosis and anti-angiogenesis by affecting key molecular pathways, such as HIF-1α, STAT3, and VEGF. However, its clinical translation is hindered by low water solubility and bioavailability, non-specific toxicity, and rapid systemic clearance. Recent advances in nanotechnology have addressed these limitations through the development of nanosized drug delivery systems, including liposomes, nanoparticles, micelles, nanogels, and other nano-formulations. These systems enhance tumor-targeted delivery, improve pharmacokinetics, and potentiate the immunomodulatory effects of SHK by reprogramming the tumor microenvironment. This review highlights the mechanisms underlying SHK antitumor immunity, evaluates the latest nanotechnology strategies to optimize SHK delivery, and discusses the challenges and prospects for translating SHK-based therapies into clinical practice.