Senescence Reprogramming by MTHFD2 Deficiency Facilitates Tumor Progression

Background Age is a critical risk factor for cancer, as its incidence and mortality increase with age. However, there's limited understanding of the molecular changes aging induces in tumors. Methods We explored demographic differences between young and old cancer patients and identified age sixty and above as pivotal in cancer prognosis. Subsequently, we developed an aging-related prognostic model based on genes to assess senescence's impact on aging-associated cancer. Results Our study revealed increased genomic instability and somatic mutations in tumors from older individuals. We also found alterations in carcinogenic signaling pathways, particularly immune responses, inflammatory pathways, and cell cycle arrest in susceptible populations. Single-cell RNA sequencing showed heightened frequencies of exhausted T cells, myeloid cells, and B cells in high-risk cohorts. Conclusion MTHFD2 emerged as a crucial molecular switch regulating senescence in cancer. Its deletion promoted tumor growth by inducing cell senescence and stimulating the senescence-associated secretory phenotype (SASP) in senescent tumor cells. This highlights the need for tailored methodologies in effective cancer management.