Nanotherapeutic Platform-Mediated Cholesterol Metabolism Regulation for Boosting Antitumor Chemo-Immunotherapy

• • Combination of COD/MTO@PLGA@FA and αPD-L1 reduced tumor-infiltrating CD8+PD-1+ T cells to 5.93%, compared to 35.9% in PBS controls (p < 0.01), demonstrating reversal of T cell exhaustion. This 6-fold reduction directly addresses a primary mechanism of immunotherapy resistance, potentially improving clinical response rates in checkpoint inhibitor-refractory patients. • • MDSC infiltration in tumor tissues decreased from 16.3% to 2.25% with the combination therapy and to 6.14% with COD/MTO@PLGA@FA alone, indicating effective inhibition of immunosuppressive cell populations. This 7.2-fold reduction in MDSCs could overcome a major barrier to chemo-immunotherapy efficacy, as MDSCs are known to suppress antitumor immunity. • • Splenic CD4+ and CD8+ T cell percentages increased from 63.4% to 72.3% and 25.7% to 32.5%, respectively, after combination treatment, reflecting robust systemic immune activation. This 8.9% and 6.8% absolute increase in helper and cytotoxic T cells suggests potential for durable antitumor memory responses, critical for preventing recurrence. • • DC maturation in tumor-draining lymph nodes reached 35.3% with COD/MTO@PLGA@FA plus αPD-L1, compared to 31.0% for MTO@PLGA, enhancing antigen presentation. This 4.3 percentage point improvement over MTO@PLGA alone underscores the added benefit of cholesterol depletion in promoting adaptive immunity, which is essential for effective chemo-immunotherapy.