Heterogeneous tumour perfusion, high vascular permeability and increased interstitial pressure are critical barriers that limit anti-cancer therapy. These intratumoral parameters are in large part a manifestation of the newly formed, angiogenic vasculature. Recently, we have demonstrated in genetically engineered mice that angiogenesis can be reversed, which normalizes tumour blood vessels, and thus effectively breaks down barriers and opens the tumour for anti-cancer therapy. Similarly, vessel remodelling in a pro-inflammatory environment can enhance lymphocyte trafficking into tumours leading to their destruction. We have engineered pro-inflammatory factors for targeted intratumoral delivery using a specific tumour-homing peptide. Our most recent findings demonstrate that low-dose tumour necrosis factor α (TNFα) when directly targeted to the tumour environment, exerts dual effects by improving vessel functionality and activating immune cells. This vascular remodelling in an inflammatory context enhances active immunotherapy and promotes tumour regression. Surprisingly, and in contrast to high dose TNFα treatment which causes vessel death, low dose intratumoral TNFα improves tumour perfusion and reduces vascular leakiness. This effect is partly mediated by re-education of intratumoral macrophages to secret anti-angiogenic factors. Thus, TNFα acts on multiple stromal cells to improve tumour perfusion, leukocyte extravasation and immune stimulation. Tumour-targeted TNFα in combination with chemotherapy is currently being tested in clinical trials. So far, combination of low dose TNFα with immunotherapy has not been explored. The potential of TNFα to increase anti-tumour immunity in the context of vascular normalization holds great promise for the development of more effective anti-cancer therapies.