PDAC carcinogenesis like all the solid tumors is mediated by the gradual build-up of driver mutations, such as the oncogene KRAS (G12D mutation) [6– 9] and the tumor suppressor gene TP53 [10, 11]. These molecular modifications are accompanied by corresponding histological alterations during different stages of PDAC development [12]. The morphological progression initiates with the formation of precursor lesions known as pancreatic intraepithelial neoplasia (PanIN) [13], which then advance to invasive adenocarcinoma. Changes in the surrounding tissue stroma occur as cancer continues to advance. The non-transformed tissue stroma, composed of components such as immunological, vascular, and connective tissue, plays a vital role in maintaining homeostasis in response to damage. However, cancer exploits these physiological responses to create a favorable tumor microenvironment (TME) for its efficient growth [12, 14]. Indeed, cancer resembles “persistent wounds”, and alterations in the stroma are the outcome of “abnormal wound healing” [15].
Immunotherapeutic strategies possess a significant capability in inducing strong immune responses against tumors. Immunomodulators, immune checkpoint blockade (ICB), and adoptive cell transfer therapy could potentially offer hopeful strategies [16 – 18]. Remarkable outcomes have been achieved from 2010 to the present through clinical research that utilizes various immunotherapeutic approaches to treat patients with different types of cancer [19 – 22]. The immune responses specifically targeting cancer cells, triggered by immunotherapy, differ from those stimulated by tumor-directed therapies. Furthermore, these responses can endure for a prolonged period even after the treatment is discontinued [23, 24]. However, the application of immunotherapy yields insufficient results for the vast majority of PDACs. This is predominantly attributed to the characteristics of its TME, which is deficient in effector T cells that have previously been exposed to antigens [25].
Tumor immunotherapy has revolutionized the treatment of various solid tumors. Nevertheless, current immunotherapies have had limited success in improving survival for patients with PDAC [26, 27]. The immunological resistance of PDAC to immunotherapies can be attributed to its low mutational burden and the hostile TME characterized by fibrosis, hypoxia, and immunosuppression [28 – 30]. However, a meta-analysis suggested that targeted immunotherapy is more effective than standard treatments in increasing survival and enhancing immune responses in pancreatic cancer patients [31]. Moreover, combining chemotherapy and surgery with other immunotherapies may synergistically improve outcomes. Various cytotoxic drugs and adjuvant therapies have been shown to sensitize the TME to immunotherapy by inducing immunogenic cell death, modifying evasive immune processes, and reducing immune suppression [32, 33].
