Pancreatic cancer (PC) is a lethal malignancy with a high mortality rate that is projected to become the second leading cause of cancer death in the next ten years [1]. Based on the GLOBOCAN 2020, it has been estimated that pancreatic cancer causes more than 466,000 deaths per year worldwide, ranking as the seventh cause of cancer death in males and females [2]. Because of the lack of early diagnosis, about 80% of patients show unresectable tumor or metastases with a 5-year survival rate of about 10%. This parameter can increase to 58% in a small percentage of patients in which tumor is detected at early stages [3]. The standard treatment for patients affected by PC is surgical resection followed by chemotherapy. This strategy, supported by different studies, results in the improvement of survival outcome. In particular, the CONKO-001 study shows that the addition of gemcitabine treatment after tumor resection results in an increased 5-years survival rate with a slight increase in the overall survival [4]. Other clinical trials are carried out in order to identify the best therapeutic regime that improves patient survival. For example, dual treatment with capecitabine and gemcitabine after tumor resection results in the amelioration of the median overall survival [5]. Another therapeutic approach that is often applied to PC patients is the administration of FOLFIRINOX (5FU, leucovorin, irinotecan and oxaliplatin). This latter strategy appears to lead to a higher overall survival, progression-free survival and response rate when compared to gemcitabine single treatment [6]. However, due to its toxicity, this therapeutic regime is not suitable for all patients making gemcitabine the standard drug used in the PC treatment [6]. Despite the advances in the understanding of pancreatic cancer pathogenesis, the causes of the insurgence of this neoplasia still remain unknown. Environmental factors, such as smoking, obesity, diabetes mellitus and chronic pancreatitis, represent a potential risk for the PC insurgence [7]. Moreover, several studies demonstrated that hereditary germline or somatic mutations are responsible for tumor progression. Particularly, mutations in genes that are associated with cell death and proliferation as well as mutations in genes associated with telomerase shortening result in PC insurgence and metastasis ^[8][9][8,9]. Apart from the alteration of tumor suppressor genes and of the ones involved in the cell cycle regulation, cytokines have been shown to have a role in the malignant transformation [10]. Chronic inflammation, indeed, can lead to the production of several cytokines that activate different signaling pathways. This cascade results in the upregulation of other proinflammatory cytokines, such as interleukin-6 (IL-6) which affect the progression of the pancreatic cancer [11]. Among these pathways, Toll-like receptors (TLRs) seem to be activated during pancreas inflammation in response to damage-associated molecular patterns (DAMPs) [12]. Upon activation, TLRs, through different pathways, lead to the transcriptional factor NF-κB which supports the inflammatory microenvironment [13]. Several studies demonstrated that TLRs are upregulated in different neoplasia such as breast, lung and colon cancer where they are associated with a favorable or with a poor prognosis [14]. Recent reports demonstrated that TLRs are highly expressed also in pancreatic cancer where they are involved in the regulation of cancer physiology and therefore, they may represent a novel target for the cancer therapy ^[15][16][17][15,16,17]. 

2. Toll-like Receptors

Toll-like receptors (TLRs) belong to the pattern recognition receptors (PRRs) family, which is involved in the activation of the innate immune response [18]. The PRRs family is able to recognize several pathogen-associated molecular patterns (PAMPs) deriving from pathogenic bacteria or fungi, viruses and protozoa [19]. TLRs consist of type I integral membrane glycoproteins with an extracellular N-terminal domain, that contains leucine-rich repeats (LRRs), and an intracellular C-terminal domain defined Toll/IL-1 receptor (TIR) domain ^[20][21][20,21]. TLRs family includes ten members: TLR1, TLR2, TLR4, TLR5, TLR6, TLR10, which are expressed extracellularly and TLR3, TLR7, TLR8, TLR9, that are expressed in the endosomes ^[22][23][22,23]. Furthermore, TLRs are classified according to the PAMPs that they are able to bind to: TLR1, TLR2, TLR4 and TLR6 recognize lipids, TLR5 and TLR10 detect proteins and TLR3, TLR7, TLR8 and TLR9 bind nucleic acids (Table 1) [24]. Upon stimulation, most of these receptors activate a signaling cascade that includes Myeloid differentiation primary response protein 88 (MyD88). This pathway, through the activation of several intermediates such as tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF-6), IL-1R-associated kinases (IRAK) and mitogen-activated kinases, leads to the activation of the transcriptional factor NF-κB [25], a pleiotropic factor involved in the activation of pro-inflammatory genes [26] (Figure 1). In addition, TLRs, in particular TLR3 and TLR4, are able to activate a non-MyD88-dependent pathway that involves TIR-domain-containing adapter-inducing interferon-β (TRIF) protein and is responsible for the synthesis of interferon (IFN) and/or NF-κB activation ^[27][28][27,28]. Defects in the activation of TLRs result in the alteration of immune homeostasis that is sustained by the upregulation of NF-κB and the production of pro-inflammatory cytokines. This contributes to the development and progression of several diseases including cancer, diabetes type 1 and autoimmune diseases ^[29][30][31][29,30,31] (Figure 1).