Pancreatic cancer, one of the most severe gastrointestinal malignancies, ranks as the fourth leading cause of tumour-related mortality worldwide (Siegel and Miller, 2022). Nanoalbumin-paclitaxel (nab-paclitaxel) treatment is one of the first-line chemotherapy regimens for pancreatic cancer. Clinical research has shown that in pancreatic cancer patients treated with nab-paclitaxel alone or in combination with other drugs (such as gemcitabine hydrochloride [GE]), the objective response rate is approximately 20%, the disease control rate is approximately 45%, the progression-free survival period is 7 months, and the overall survival period is 12 months (Bittoni et al., 2021). Although combination treatment with nab-paclitaxel and GE has yielded the largest increase in survival, this regimen is characterized by substantial toxicity and is often restricted to patients that exhibit good performance. Therefore, novel therapies with improved efficacy are needed to improve patient outcomes.

Nab-paclitaxel is mainly administered through intravenous injection. Nab-paclitaxel in blood must pass through vascular endothelial barriers before it can be absorbed by pancreatic cancer cells. Endothelial cells (ECs) are the first barrier to the subintima for substances in the circulation. Circulating substances can be deposited into the subintima through only two pathways: crossing the 3–6 nm endothelial junction through free diffusion (observed for compounds such as water and small molecules) (Simionescu et al., 1978) and penetrating cells to reach the subendothelium (observed for, for example, macromolecules) (Frank et al., 2009). Clinical nab-paclitaxel contains a hydrophobic covalent bond between albumin and paclitaxel and is 130 nm in size (Desai et al., 2006). After intravenous infusion, nab-paclitaxel dissociates into 10–30 nm particles (Giordano et al., 2017). Since the intercellular space is smaller than the diameter of a circulating nab-paclitaxel molecule and is covered by a negatively charged glycocalyx (Alphonsus and Rodseth, 2014), the trafficking of nab-paclitaxel particles across intact endothelial barriers can be accomplished only via transcytosis.

Transcytosis is a mechanism in which macromolecular cargo (e.g., albumin in the blood) is endocytosed by a discrete membrane-bound vesicle from one side of polar cells (e.g., within the lumen) and then trafficked to the other (e.g., basolateral side), followed by exocytosis of the macromolecular cargo (Frank et al., 2009; Wu et al., 2016). CAV1 is a critical caveolar component that indicates the formation of lipid vesicles by small plasma membrane invaginations (Parton and del Pozo, 2013). The upregulation of CAV1 increases the number of caveolae in the cell membrane, whereas CAV1 knockdown decreases the number of caveolae (Bai et al., 2020; Razani et al., 2002). CAV1 controls a variety of processes, such as cell cycle progression, growth and survival signaling, anabolism, cytoskeletal dynamics, and tumour cell invasion. However, its effects can be highly contextual (sometimes contradictory) and depend on the cancer cell type and disease stage (Bernatchez, 2020; Kamposioras et al., 2021; Lolo et al., 2020).

At present, the mechanisms of nab-paclitaxel transcytosis across ECs in pancreatic tumour tissues are not completely known. The hypoxic microenvironment is an important feature of malignant solid tumours and increases the difficulty of tumour treatment (Wang et al., 2021). A previous study revealed that autophagy can be activated in a hypoxic microenvironment. Macroautophagy/autophagy is a homeostatic process in which cytoplasmic structures are engulfed by double-membrane vesicles called autophagosomes, which subsequently fuse with lysosomes for destruction (Marino et al., 2014). HIF1α functions as a transcription factor and undergoes degradation through an oxygen-dependent mechanism, thereby enabling swift adaptation and survival in hypoxic environments. AMP-activated protein kinase α (AMPKα), a cellular energy charge sensor, can be activated in response to hypoxic stimulation to compensate for the reduction in mitochondrial respiration. In a hypoxic environment, the activation of HIF1α and AMPKα can directly initiate the formation of autophagosomes by enhancing the formation of the ATG12-ATG5 complex (Hu et al., 2012).

In the present study, we aimed to address the mechanism of nab-paclitaxel transcytosis across vascular ECs and develop novel strategies to improve the therapeutic efficacy of nab-paclitaxel in pancreatic cancer. We found that hypoxia enhanced the autophagic degradation of CAV1, decreased the abundance of caveolae, and consequently suppressed nab-paclitaxel transcytosis across ECs. Suppressing CAV1 autophagic degradation is a novel translatable strategy for enhancing nab-paclitaxel chemotherapeutic activity in the treatment of pancreatic cancer.