The tumor microenvironment (TME) is a complex and dynamic ecosystem that plays a pivotal role in cancer progression and therapy resistance. Its heterogeneity and constant remodeling present significant challenges for effective treatment. The emergence of nanomedicine integrates nanotechnology and medicine, aiming to overcome and ameliorate the limitations of conventional therapeutic agents in cancer treatment. Despite the broad biomedical applications of nanomaterials, the clinical translation of nanodrugs remains hindered by the complexity and heterogeneity of the TME as well as challenges related to the physicochemical properties of nanomaterials. This paper published in iMetaMed underscores key challenges and difficulties currently faced by nanomaterials in cancer treatment, including: issues related to nanomaterial biosafety and long-term toxicity assessment; uncertainties in vivo biotransformation and metabolic pathways; therapeutic efficacy variations caused by spatiotemporal heterogeneity of the TME; barriers from laboratory research to clinical translation; and insufficient selectivity in the precise modulation of TME components.