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Abstract The tumor microenvironment (TME) plays a key role in cancer development and emergence of drug resistance. TME modulation has recently garnered attention as a potential approach for reprogramming the TME and resensitizing resistant neoplastic niches to existing cancer therapies such as immunotherapy or chemotherapy. Nano-based solutions have important advantages over traditional platform and can be specifically targeted and delivered to desired sites. This review explores novel nano-based approaches aimed at targeting and reprogramming aberrant TME components such as macrophages, fibroblasts, tumor vasculature, hypoxia and ROS pathways. We also discuss how nanoplatforms can be combined with existing anti-tumor regimens such as radiotherapy, immunotherapy, phototherapy or chemotherapy to enhance clinical outcomes in solid tumors.