The T‐Cell Response Mechanism in Human Papillomavirus‐Associated Cervical Cancer and New Strategies for Immunotherapy

ABSTRACT Human papillomavirus (HPV) is a double‐stranded DNA virus that infects human skin and mucosal tissues exclusively. The German scientist Harald zur Hausen was awarded the 2008 Nobel Prize in Physiology or Medicine for his discovery of the link between HPV infection and cervical cancer. Indeed, HPV is implicated in approximately 96%–99.7% of cervical cancer cases, and is also a major etiological factor in other malignancies, including oropharyngeal, head and neck, and penile cancers. Although prophylactic HPV vaccines are effective in preventing HPV‐related cancers, particularly cervical cancer, they do not cover all oncogenic HPV types and offer limited therapeutic benefit against pre‐existing infections. Other immunotherapies, such as immune checkpoint inhibitors (ICIs), also face challenges, including low response rates and significant patient heterogeneity. Consequently, HPV‐associated tumors remain a significant public health burden. Recent advances highlight the crucial role of T cells in the immune response against HPV infection. T‐cell‐based immunotherapies, including adoptive T‐cell therapy and therapeutic vaccines, are emerging as promising approaches that complement conventional treatments such as surgery, radiotherapy, and chemotherapy. These strategies primarily aim to reverse the immunosuppressive tumor microenvironment (TME) in HPV‐associated tumors and activate a durable antitumor immune response. However, key challenges persist, including enhancing the efficacy and safety of existing therapies and optimizing strategies to account for individual patient heterogeneity. Therefore, an in‐depth exploration of the T‐cell response mechanism triggered by HPV infection is essential. Coupled with strategies to optimize T‐cell activation and functional maintenance, such insights are critical for developing more effective therapeutic vaccines and cellular immunotherapies to overcome current treatment limitations. This review focuses on T‐cell response mechanisms in HPV‐driven cervical cancer and associated cell‐based therapeutic strategies, aiming to provide new perspectives for future research and clinical management of HPV‐associated cancers.