Engineering immunity in osteosarcoma: nanomedicine strategies for overcoming immune evasion

Abstract

Osteosarcoma is an aggressive malignancy characterized by inherent chemoresistance, a high propensity for pulmonary metastasis, and dismal survival rates in patients with advanced or refractory disease. While immunotherapy has revolutionized cancer treatment, its efficacy in osteosarcoma remains severely limited by an immunologically “cold” and profoundly immunosuppressive tumor microenvironment (TME). This TME is defined by pervasive infiltrates of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and a dense mineralized extracellular matrix (ECM) barrier that collectively exclude or exhaust cytotoxic T cells. We examine the intricate mechanisms driving this immunotherapy resistance at the cellular and molecular levels. We then explore how rationally designed nanotechnology platforms can overcome these barriers. Specifically, we review targeted nanomedicine delivery systems engineered to home to bone tissue and reshape the TME landscape via strategies including TAM reprogramming, MDSC depletion, ECM clearance to relieve physical resistance, and activation of innate immune pathways. Unlike general immunotherapy reviews, the main contribution of this mini-review is strictly focused on innovative nanomedicine delivery platforms—specifically biomimetic, stimuli-responsive, and bone-targeted systems. We dissect how these rationally engineered platforms overcome the unique physical and cellular barriers of the osteosarcoma TME, with a critical emphasis on the severe translational hurdles, such as protein corona formation and in vivo stability, that limit clinical progression. In conclusion, multi-targeted nanomedicine delivery systems hold strong preclinical potential to provide a novel framework for advancing osteosarcoma treatment by precisely modulating the TME and eliciting durable antitumor immune responses.