Senescence Reprogramming by MTHFD2 Deficiency Facilitates Tumor Progression

Age is a critical risk factor for cancer, as its incidence and mortality increase with age. However, there is limited understanding of the molecular changes aging induces in tumors. 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. Grounded in the coefficients and expression levels of these identified signature genes, a risk score was computed, enabling the classification of collected samples into aging-related high-risk and low-risk cohorts. 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. 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.