Osteosarcoma (OSA) is an aggressive primary bone cancer mainly affecting the pediatric population. Despite intensive multimodal treatments, therapeutic progress has remained limited for decades, resulting in high recurrence rates, poor prognosis driven by metastatic progression, and severe chemotherapy-associated toxicities. To advance the development of more effective and safer therapeutic strategies, our recent studies identified Chondroitin Sulfate Proteoglycan (CSPG)4 as a relevant mediator of the malignant behavior of OSA cells. Targeting CSPG4 DNA-based vaccine demonstrated encouraging antitumor activity against OSA. Nevertheless, since single-agent immunotherapies are often constrained by tumor immune escape, the need for rational combinatorial strategies is of utmost importance. In this perspective, we broaden our analysis to include other potentially complementary targets beyond CSPG4, which may contribute to OSA pathogenesis. Among these, the cystine/glutamate antiporter xCT and Toll-like Receptor 2 (TLR2) emerge as particularly promising due to their established role in tumor progression, therapy resistance, and immune modulation. We discuss the contribution of all these molecules in major hallmarks of OSA—(1) proliferative and survival advantages, (2) metastasis and angiogenesis, and (3) immune evasion—and examine potential strategies for their combined targeting. By leveraging knowledge gained from other cancer models and integrating it with the distinct biological and clinical features of OSA, this perspective seeks to outline rational and innovative combinatorial strategies that may overcome current therapeutic limitations and ultimately improve patient outcomes.
骨肉瘤是一种侵袭性原发性骨癌，主要影响儿童群体。尽管采用强化多模式治疗，数十年来其治疗进展仍然有限，导致高复发率、转移进展驱动的预后不良以及严重的化疗相关毒性。为推进更有效且安全的治疗策略开发，我们近期研究发现硫酸软骨素蛋白聚糖4是骨肉瘤细胞恶性行为的关键介质。靶向CSPG4的DNA疫苗在对抗骨肉瘤方面展现出令人鼓舞的抗肿瘤活性。然而，由于单药免疫疗法常受肿瘤免疫逃逸机制制约，制定合理的联合治疗策略显得尤为重要。基于此视角，我们将分析范围扩展至CSPG4之外其他可能具有互补作用的潜在靶点，这些靶点可能参与骨肉瘤的发病机制。其中，胱氨酸/谷氨酸逆向转运蛋白xCT与Toll样受体2因其在肿瘤进展、治疗抵抗和免疫调节中的明确作用而显得尤为突出。本文系统探讨了这些分子在骨肉瘤三大核心特征——（1）增殖与生存优势，（2）转移与血管生成，（3）免疫逃逸——中的具体作用机制，并深入研究了联合靶向这些分子的潜在策略。通过整合其他癌症模型的研究成果，并结合骨肉瘤独特的生物学与临床特征，本文旨在构建合理创新的联合治疗策略框架，以期突破当前治疗瓶颈，最终改善患者预后。
肿瘤(癌症)患者之家