Figure 4: Tumour and immune cells plasticity in therapy-induced tumour tissue damage and development of therapy resistance. Immune cells polarization, soluble mediators, and extracellular matrix components of the tumour microenvironment contribute to progression and liver metastasis by constructing the so-called “premetastatic niche.” Therapy-induced tumour tissue injuries lead to interconnected phenotypic alterations of tumour and immune cells. Activity of several drugs (5-FU; gemcitabine and other cytotoxic agents) on (the) malignant cells can be associated with the concomitant TAMs and MDSCs activation or expansion due to enhanced polarization and phenotypic plasticity in metastatic tissues. Consistent with this hypothetical model, extensive tumour tissue injuries and necrosis activate the “inflammasome” and enhance the release of cytokines (IL-1 ) and growth factors (TGF- ) and likely activate immune-suppressive pathways mediated by adenosine production (purinergic pathways). In addition, tumour tissue damage, following cytoreductive therapy, results in epigenetic alterations, DNA damage response, increased expression of drug transporters, and DNA-repair enzymes in malignant cells which contribute to protect against cytotoxic drugs and result in therapy resistance and tumour relapse.