Investigation of P53 Roles and the Probability of Cell–Cell Interactions in the Tumour Microenvironment During Radiotherapy

Background: Radiotherapy remains a cornerstone of cancer treatment, administered to approximately 40–50% of cancer patients, yet therapeutic failure and tumor recurrence represent major clinical challenges. In colorectal cancer, despite initial tumor regression following radiotherapy, a substantial proportion of patients experience disease recurrence, with failure rates reaching 50% in high-risk cases such as advanced prostate cancer. The tumor suppressor protein p53, encoded by the TP53 gene, plays a pivotal role in orchestrating cellular responses to ionizing radiation through regulation of DNA damage repair, cell cycle arrest, apoptosis, and senescence. Mutations in TP53, occurring in approximately 60% of locally advanced rectal cancers, are associated with inferior pathological tumor regression (23% versus 36% in wild-type cases, p = 0.05) and compromised progression-free survival [1,2]. While the cell-autonomous effects of p53 loss on radioresistance have been extensively documented, the non-cell-autonomous mechanisms—specifically, how p53-deficient cells communicate with wild-type neighbors within the tumor microenvironment—remain poorly understood. Emerging evidence suggests that intercellular communication may fundamentally reshape radiation responses and enable therapy-resistant subpopulations to survive and proliferate [3,4]. Hypothesis: We hypothesized that cross-talk between p53 wild-type (WT) and p53 knockout (KO) colorectal cancer cells within the tumor microenvironment modulates radiotherapy responses. Specifically, we propose that p53 KO cells, lacking the canonical DNA damage response pathways governed by functional p53, secrete factors that alter the radiation sensitivity of neighboring WT cells, thereby contributing to therapeutic resistance and tumor recurrence [5,6]. Aims: The primary aims of this study were twofold: (1) to establish the existence and characterize the nature of cross-talk between p53 WT and p53 KO colorectal cancer cells in the context of radiotherapy, and (2) to evaluate the impact of this intercellular communication on radiotherapy outcomes, including clonogenic survival, cell fate determination, and the potential for therapeutic intervention to reverse resistance mechanisms.