A TLR4 Agonist Induces Osteosarcoma Regression by Inducing an Antitumor Immune Response and Reprogramming M2 Macrophages to M1 Macrophages

Simple Summary Due to the lack of progress in OsA's treatment and survival, there is a need to develop new therapeutic approaches for this tumor. OsA is a complex tumor for which the immune microenvironment appears as a potential therapeutic option. This study explores the antitumor effect of a chemically detoxified TLR4 agonist MP-LPS, under liposomal formulation called Lipo-MP-LPS. The agent induces a significant antitumor response and inhibition of tumor growth in an immunocompetent OsA model. Lipo-MP-LPS acts by favoring the switch of M2 macrophages to M1, and promotes T-cell recruitment. The study suggests that Lipo-MP-LPS could be used alone or in combination with other therapies for refractory tumors like OsA.Abstract Osteosarcoma (OsA) has limited treatment options and stagnant 5-year survival rates. Its immune microenvironment is characterized by a predominance of tumor-associated macrophages (TAMs), whose role in OsA progression remain unclear. Nevertheless, immunotherapies aiming to modulate macrophages activation and polarization could be of interest for OsA treatment. In this study, the antitumor effect of a liposome-encapsulated chemically detoxified lipopolysaccharide (Lipo-MP-LPS) was evaluated as a therapeutic approach for OsA. Lipo-MP-LPS is a toll-like receptor 4 (TLR4) agonist sufficiently safe and soluble to be IV administered at effective doses. Lipo-MP-LPS exhibited a significant antitumor response, with tumor regression in 50% of treated animals and delayed tumor progression in the remaining 50%. The agent inhibited tumor growth by 75%, surpassing the efficacy of other immunotherapies tested in OsA. Lipo-MP-LPS modulated OsA's immune microenvironment by favoring the transition of M2 macrophages to M1 phenotype, creating a proinflammatory milieu and facilitating T-cell recruitment and antitumor immune response. Overall, the study demonstrates the potent antitumor effect of Lipo-MP-LPS as monotherapy in an OsA immunocompetent model. Reprogramming macrophages and altering the immune microenvironment likely contribute to the observed tumor control. These findings support the concept of immunomodulatory approaches for the treatment of highly resistant tumors like OsA.