Current cancer treatment strategies continue to face significant challenges, primarily due to tumor relapse, drug resistance, and low treatment efficiency. These issues arise because certain tumor cells adapt to the host immune microenvironment and evade the immune system. This study presents a new cancer immunotherapy strategy using serum-based antibodies from mice exposed to mouse cutaneous squamous cell carcinoma (mCSCC). The experiment was conducted in three stages. In the first stage, mCSCC cells were isolated and expanded cultured from DMBA/TPA-induced mCSCC. In the second stage, these expanded tumor cells were injected into healthy mice to stimulate the production of anti-tumor antibodies. In the final stage, therapeutic serum was extracted from these healthy mice and reintroduced into the tumor-bearing mice. An ELISA assay was utilized to analyze the levels of p53, Bcl-xL, NF-κB, and Bax. The results showed that the serum treatment not only reduced tumor volume but also reversed changes in p53, Bcl-xL, NF-κB, and Bax. In conclusion, this study developed a new immunotherapeutic strategy for treating mCSCC. However, further research is needed to fully comprehend the mechanism of this serum treatment.