Lactate-mediated immune suppression and MDSC expansion in endometriosis: Mechanisms and nanoparticle-targeted...

Endometriosis, a chronic gynecological disorder characterized by the ectopic growth of endometrial-like tissue, is associated with severe pelvic pain, infertility, and profound immune dysregulation. Despite advances in hormonal therapy and surgical intervention, current treatments often fail to address the underlying pathophysiology and carry significant side effects, leading to frequent recurrence. Emerging evidence implicates metabolic reprogramming-particularly the pathological accumulation of lactate-as a key driver of disease progression. Elevated lactate levels create a persistently acidic microenvironment that promotes immune suppression, angiogenesis, and fibrosis, largely through the recruitment and activation of myeloid-derived suppressor cells (MDSCs). These immunosuppressive cells enable lesion immune evasion, support neovascularization, and contribute to chronic inflammation, making the lactate-MDSC axis a critical therapeutic target. In this review, we propose an innovative nanomedicine-based approach to disrupt this pathogenic cycle. Our design involves targeted nanoparticles (NPs) engineered to home in on the aberrant vasculature of endometriotic lesions via ligand-mediated recognition. To achieve site-specific action, the NPs are equipped with pH-sensitive linkers that enable controlled drug release within the acidic lesion microenvironment. This platform is capable of co-delivering an anti-lactate agent to neutralize metabolic acidosis and a proven anti-endometriosis drug to suppress lesion growth and inflammatory signaling. By simultaneously reversing lactate-driven immunosuppression and directly inhibiting lesion viability, this dual-targeted system offers a multifaceted therapeutic strategy. Preclinical evidence supports the feasibility of targeting both metabolic and immune pathways in endometriosis. However, further research is needed to optimize NP formulation, enhance vascular targeting specificity, and evaluate safety and efficacy in clinical settings. Targeting the lactate-MDSC axis with precision nanomedicine has the potential to transform endometriosis management, offering a more effective, durable, and less invasive alternative to current therapies.