Immunotherapies, signal transduction inhibitors and chemotherapies can successfully achieve remissions in advanced stage cancer patients, but durable responses are rare. Using malignant melanoma as a paradigm, we propose that therapy-induced injury to tumour tissue and the resultant inflammation can activate protective and regenerative responses that represent a shared resistance mechanism to different treatments. Inflammation-driven phenotypic plasticity alters the antigenic landscape of tumour cells, rewires oncogenic signalling networks, protects against cell death and reprogrammes immune cell functions. We propose that the successful combination of cancer treatments to tackle resistance requires an interdisciplinary understanding of these resistance mechanisms, supported by mathematical models.