Pleiotropic mechanisms in the tumour microenvironment (TME). (a) Drug loaded NPs can inhibit the hypoxic tumor vasculature of colorectal cancer by targeting and reprogramming the multiple mechanisms: i) Myeloid-Derived Suppressor Cells (MDSCs) and T-regulatory cells (Tregs) inhibit cytotoxic T-lymphocytes (CTL) and drive tumour growth. ii) The conversion of M₁ macrophages to M₂ macrophages also leads to tumor growth. iii) TGFβ-induced fibroblasts activate Cancer-Associated Fibroblasts (CAFs), which promote tumor progression. iv) VEGF also stimulates abnormal tumour vasculature and cancer development. Drug loaded NPs can target all of these pathways to suppress tumour growth. NPs can reprogram M₂ macrophages into M₁ phenotypes, which reactivate the immune response and inhibit tumour growth. Drug loaded NPs can also activate mature DCs, leading to the activation of B cells through T cells and the production of antibodies that can target and eradicate tumour cells. These NP-stimulated pathways can thus overcome the inhibitory effects exerted by MDSCs on mature dendritic cells (DCs) and the inhibitory effects of Tregs on INF-γ, thus killing tumour cells. Additionally, NPs loaded with oxygen can inhibit the hypoxic tumour vasculature by inducing oxygen, thus reversing hypoxia and limiting tumour growth [29]. (b) Schematic representation of how drug-loaded nanoparticles modulate tumor-associated macrophages (TAMs) under hypoxic conditions. NPs inhibit TAM2 and promote TAM1 polarization, leading to increased IL-12 and decreased IL-10 production, which suppresses tumour vasculature and enhances anti-tumor immunity. Drug-loaded NPs can inhibit the conversion of TAM₁ to TAM₂ and reduce tumour growth. SiRNA-loaded NPs can also suppress TAM2 activity [30].