## 1 Introduction  
Pancreatic cancer (PaCa) is one of the most lethal malignancies of the digestive tract, owing to its often late-stage diagnosis, the absence of effective therapies, and the unpredictable nature of disease progression [1,2]. Both local and systemic inflammation have been implicated as factors that contribute to promoting PaCa growth and dissemination [3]. The relationship between inflammation and PaCa carcinogenesis is mediated by the infiltration of inflammatory cells into the tumor microenvironment (TME) [4]. In the PaCa TME, M1 macrophages, dendritic cells (DCs), and effector CD4+ and CD8+ T lymphocytes are less abundant than myeloid-derived suppressor cells (MDSCs), M2-polarized macrophages, and regulatory T lymphocytes (Treg) [5]. This immunological microenvironment favors tumor growth, and the TME may acquire additional immunosuppressive properties. In this setting, cancer cell survival may be supported by a proinflammatory environment, potentially leading to the establishment of a dynamic and metabolically symbiotic TME [4]. Soluble inflammatory cytokines serve as key messengers for facilitating interactions between immune and cancer cells [3]. Proinflammatory mediators such as interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-\(\alpha\)), anti-inflammatory IL-10, and transforming growth factor-beta (TGF-\(\beta\)) are among the major inflammatory factors in this immunomodulatory network [3].  
The extracellular release of mitochondrial-derived damage-associated molecular patterns (mtDAMPs), including circulating cell-free mitochondrial DNA (ccf-mtDNA), has been described across various pathological conditions, including cancer, and is associated with systemic sterile inflammation [6; 7; 8; 9]. Despite the evolutionary compartmentalization of DNA within the nucleus and mitochondria, the release and subsequent accumulation of both nuclear and mtDNA in the cytosol has been documented in pathological conditions. In particular, the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway mediates the release of mtDNA into the cytosol, where it triggers ferroptosis [6; 7; 8]. In this context, cytosolic and extracellular mtDNA becomes a potent stimulator of inflammation, regulating biological processes integral to cell proliferation and survival [6; 7; 9]. The inflammation induced by mtDNA release contributes to the amplification of tissue and organ damage [8; 10; 11]. By acting as an mtDNA, cf-mtDNA promotes neutrophil migration and degranulation at sites of injury, thereby contributing to cellular damage and the initiation of local inflammatory responses [11]. Interestingly, [PERSON] et al. [8] have demonstrated that M1 pancreatic resident macrophages secrete extracellular vesicles (EVs) containing mitochondria, which exhibit proinflammatory properties and can enter pancreatic \(\beta\) cells. These mitochondria-derived EVs induce lipid peroxidation and mitochondrial damage [8].  
Recently, the detection and quantification of ccf-mtDNA in biological fluids of cancer patients have garnered significant interest as a potential approach for identifying diagnostic and prognostic biomarkers. For instance, lower ccf-mtDNA levels have been reported in the plasma of women with breast cancer compared with healthy controls [12]. In contrast, elevated ccf-mtDNA levels have been observed in the serum of patients with bladder, prostate, renal cell, and testicular cancers [13; 14]. Increased ccf-mtDNA levels have also been described in women with epithelial ovarian cancer relative to peers with benign ovarian conditions and healthy controls [15]. However, no studies have investigated whether the sterile inflammatory milieu of PaCa is linked to the release of cellular proinflammatory components, particularly ccf-mtDNA, or whether the nature of such components contributes to distinct inflammatory profiles in PaCa patients. To address this gap in knowledge, we quantified ccf-mtDNA levels in PaCa patients and examined their association with patient inflammatory profiles.