Pancreatic ductal adenocarcinoma (PDAC) is a truly lethal malignancy worldwide. This indisposed prognosis of PDAC is a direct consequence of inherent and rapidly acquired resistance to nearly all forms of conventional therapy, and an aggressive metastatic ability [1]. The cellular and molecular basis of this therapeutic failure is a complex and dynamic process within the PDAC-microenvironment (PDAC-ME), which consists of a dense, fibrotic, and hypoxic milieu, populated by pancreatic stellate cells (PSCs), cancer-associated fibroblasts (CAFs), tumor associated macrophages (TAMs), tumor associated dendritic cells (DCs), and myeloid derived suppressor cells (MDSCs) [2]. Within this PDAC-ME, intercellular communication is the central mediator of tumor progression, facilitating the complex interplay that drives immune evasion, drug resistance, and metastasis. This communication was primarily limited to soluble factors like cytokines and direct cell-cell contact [3]. Recent studies have demonstrated that extracellular vesicles mediate intracellular communication within PDAC-ME, with exosomes being the most notable.

Exosomes are nanosized (50 −150 nm) subtype of extracellular vesicles typically originate from the multivesicular bodies (MVBs), secreted into the extracellular space by fusion of the MVB with the plasma membrane. This distinct biogenesis pathway differentiates them from larger microvesicles (100–1000 nm), which bud directly from the plasma membrane. Exosomes are characterized by the manifestation of tetraspanins CD63, CD9 and CD81, which are frequently used makers for exosome identification and isolation [4]. In the context of PDAC, recent studies have focused on profiling of PDAC-derived exosomes for metabolic signature [5], genes associated with prognosis [6] and risk associated genes [7]. These studies highlight that exosomes derived from PDAC carry a unique repertoire of biomolecules that can serve as potential therapeutic targets and biomarkers.

Exosomes are released from diverse cell types, including cancer cells [8]. They are loaded with proteins, lipids, and an array of nucleic acids such as mRNAs, miRNAs, long non-coding RNAs (lncRNAs), and DNA fragments reflecting their parental cells [9]. They deliver their functional cargo to recipient cells through endocytosis, phagocytosis, or direct membrane fusion [10]. Within the recipient cell, they reprogram its phenotype and function.

In the context of cancer advancement, exosomes derived from primary tumor establish a premetastatic niche and prepare distant organs for metastatic colonization, induce therapeutic resistance, and mount a formidable defense against immune surveillance [11]. In addition to niche formation, exosomes actively promote local invasion by transferring proteins and miRNAs that induce an epithelial-to-mesenchymal transition (EMT) [12]. This process supports the cells with migratory and invasive properties [13], suppressing tumor suppressor genes in recipient cells and inducing new blood vessel formation by transferring pro-angiogenic factors and growth factors that suppress anti-angiogenic pathways [14]. This stimulates the formation of neovessels in the growing tumor to provide essential nutrients and to conduit systemic dissemination.

A defining characteristic of PDAC is its profound intrinsic and acquired resistance to chemotherapy. Exosomes are indispensable contributors to this multifaceted resistance [15]. PDAC cells reduce local drug concentration below the therapeutic threshold by encapsulating cytotoxic drugs within exosomes, actively expelling them from the cells, and effectively limiting their impact [16]. More insidiously, exosomes mediate resistance by transferring specific biomolecules that reprogram drug-sensitive recipient cells into a resistant phenotype [17]. Exosomes can alter antitumor immunity by immunomodulating key immune effector cells by directly inducing T-cell apoptosis [18] or anergy and polarizing and recruiting immunosuppressive cell populations [19]. This intercellular transfer of resistance is a formidable clinical challenge.

The pathogenic roles of exosomes are overwhelming; their unique biological properties also present extraordinary opportunities for clinical application [20]. Their stability, molecular status, and a real-time snapshot of the parent tumor cell make them ideal candidates for "liquid biopsy" applications [21]. Even more exciting is the potential to harness exosomes as therapeutic delivery vehicles [22]. Exosomes derived from non-malignant cells, or those that have been bioengineered, represent a novel class of nanocarriers [23], [24]. Unlike synthetic nanoparticles, they possess low immunogenicity, inherent biocompatibility, and an innate capability to cross biological barriers [25]. Exosomes derived from tumor suppressive immune cells are potent antitumor agents, carry cytotoxic proteins, and deliver them to cancer cells to induce apoptosis [26]. Besides, exosomes can be designed to carry therapeutic payloads like conventional chemotherapeutics, siRNAs, and novel immunomodulators. Their surfaces can be decorated with targeting ligands to enhance targeted delivery to tumor cells, maximizing efficacy and minimizing systemic toxicity [27]. Using a biological system to deliver targeted therapy holds immense promise for improving outcomes.

This review will comprehensively dissect the multifaceted functions of exosomes in PDAC, focusing on three cardinal features of the disease: acquired therapy resistance, immune evasion, and metastasis. Furthermore, we will explore the remarkable biology of exosomes by shifting focus from their pathological roles to next-generation diagnostic biomarkers and therapeutic vehicles. By examining how exosomes can both contribute to disease progression and be the potential key to its unravelling, this review provides a holistic perspective to fight against this devastating cancer.