Cellular senescence refers to a state in which cells enter a permanent cell cycle arrest without undergoing cell death. Cells become senescent after being exposed to replicative, genotoxic, oncogenic, and/or oxidative stress. Senescence has long been considered a tumor-suppressive mechanism that prevents the malignant transformation and uncontrollable proliferation of cells carrying an unstable genome and/or activated oncogenes. Therapy-induced senescence (TIS), the induction of senescence in tumors through radiation and/or certain chemotherapy treatments, is thought to contribute to the anti-tumor effects of cancer treatments. Various mechanisms that induce tumor cell senescence are extensively examined in this thesis. I first demonstrated the DNA repair-independent role of DNA-PKcs and detailed how inhibition of DNA-PKcs accelerates senescence by resulting in persistent DNA damage foci and mitotic slippage in response to radiation. Then I explored the roles of telomerase catalytic activity in DNA damage response and senescence. According to the results, using a novel covalent TERT inhibitor NU-1 and the well-established antagonists BIBR-1532 and MST-321 to target telomerase catalytic activity enhanced cellular senescence by delaying end-joining repair of DNA double-strand breaks induced by radiation. In the syngeneic CT26 murine colon carcinoma tumor model, NU-1 did not affect the host or reduce tumor growth on its own, but it significantly enhanced activated immune infiltrate and exhibited immunogenic radiosensitization over radiation alone. This study points to TERT as an attractive target for overcoming intrinsic resistance to genotoxic therapy and potentiating anti-tumor immune response. In the next chapter, I discussed the possibility of using senescent tumor cells as a cancer vaccine for controlling tumor growth and metastasis, including how the senescence vaccine synergizes radiation and immune checkpoint inhibitors. Senescent tumor cells have been shown to promote dendritic cell maturation/activation and T cell priming, thereby enabling dendritic cells activated by senescent tumor cells to serve as cancer vaccines for treating both local and metastatic tumors. This work may offer translational benefits from using senescent tumor cells to enhance anti-tumor immunity and improve cancer treatment. Paradoxically, a growing body of preclinical studies indicates that accumulated senescent cells in tumors may also promote tumor recurrence, metastasis, and resistance to therapy. The utilization of senolytics, a class of chemical compounds that specifically eliminate senescent cells, might be a promising approach to inhibit senescence-mediated detrimental effects. Senolytic compounds such as ABT263, a BCL-2 inhibitor, were commonly used following senescence induction in preclinical studies, referred to as the "one-two punch" strategy. Here, I demonstrated that senescent tumor cells induced by various inducers displayed varying sensitivity to ABT263-induced apoptosis. Interestingly, senescent cells displayed bystander effects, causing neighboring non-senescent cells to become more sensitive to senolytic treatment, whereas the degree of bystander effect was positively correlated with senescent cells' sensitivity to senolytic compounds. This work suggested that evaluating senescence hallmarks and/or manipulating therapy-induced senescence might be necessary to improve the efficacy of "one-two punch" cancer therapy.