Simple SummaryAcquired resistance to chemoradiotherapy is the common cause of relapse in cancer treatments. Although chemoradiotherapy often produces promising results early in treatment, most cancer patients develop resistance in the later stages and succumb to the disease. In this review, we attempt to explain how cancer cells exploit the tumour suppressor p53 to activate various cytoprotective mechanisms such as DNA damage response, immediate early response gene 5/heat-shock factor 1 pathway, and p21/nuclear factor erythroid 2–related factor 2 pathway to protect themselves from the cytotoxic/genotoxic effects of radiation and drugs. These cytoprotective pathways protect cancer cells by repairing damaged-DNA, maintaining cell homeostasis, reducing oxidative stress, and eliminating drugs from the cells, ultimately resulting in resistance to chemoradiotherapy.AbstractResistance to chemoradiotherapy is the main cause of cancer treatment failure. Cancer cells, especially cancer stem cells, utilize innate cytoprotective mechanisms to protect themselves from the adverse effects of chemoradiotherapy. Here, we describe a few such mechanisms: DNA damage response (DDR), immediate early response gene 5 (IER5)/heat-shock factor 1 (HSF1) pathway, and p21/nuclear factor erythroid 2–related factor 2 (NRF2) pathway, which are regulated by the tumour suppressor p53. Upon DNA damage caused during chemoradiotherapy, p53 is recruited to the sites of DNA damage and activates various DNA repair enzymes including GADD45A, p53R2, DDB2 to repair damaged-DNA in cancer cells. In addition, the p53-IER5-HSF1 pathway protects cancer cells from proteomic stress and maintains cellular proteostasis. Further, the p53-p21-NRF2 pathway induces production of antioxidants and multidrug resistance-associated proteins to protect cancer cells from therapy-induced oxidative stress and to promote effusion of drugs from the cells. This review summarises possible roles of these p53-regulated cytoprotective mechanisms in the resistance to chemoradiotherapy.