When stress spreads: Transmissible ER stress as a driver of immune remodeling in PDAC

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year survival rate of only 11%. Within the PDAC tumor microenvironment (TME), rapidly proliferating tumor cells outgrow the vascular supply, creating hostile microenvironmental conditions such as nutrient deprivation, hypoxia, and high metabolic demand. This, in turn, perturbs the protein folding capacity of the endoplasmic reticulum (ER), thereby provoking a cellular state of ‘ER Stress'. Also, tumor cells can disseminate ER stress to the stromal cells within the TME in a process known as ‘transmissible ER stress'. Although PDAC is considered an immunologically ‘cold' tumor, ER stress appears to rewire the host immune system for tumor cell immune evasion. In this regard, we determined if the bone marrow-derived macrophages (BMDM) are susceptible to “transmissible” ER stress. Herein, murine pancreatic Panc02 and KPC cells (transmitter cells) were treated with thapsigargin (Tg), and the ER stress-conditioned medium was used to culture the murine BMDMs (receiver cells). Our preliminary data demonstrated that BMDMs cultured in ER-stress-conditioned medium demonstrated a significant transcriptional upregulation of proinflammatory modulators, including iNOS , IRE1 alpha / Xbp1 , nuclear factor-kappaB ( NF-κB ), and cyclooxygenase-2 ( COX-2 ). Strikingly, this inflammatory state co-occurred with increased Arg1 , consistent with an immunosuppressive, tumor-promoting macrophage phenotype. Altogether, this transcriptional profile reflects a hybrid inflammatory-immunoregulatory state characteristic of PDAC tumor-associated macrophages (TAMs). To delineate the mechanism by which transmissible ER stress modulates the immune profile of BMDMs, we propose genetic ablation and/or pharmacological inhibition of the classical stress pathways, including IRE1alpha, PERK, and ATF6, to determine their effect on BMDM polarization. In conclusion, our findings provide new insights into the dynamic crosstalk between PDAC cells and BMDMs, highlighting two key aspects: a) the complexity underlying the concurrent pro-inflammatory and immunosuppressive features within the TME following ER stress, and b) raises the possibility that this phenomenon may contribute to the attenuation of intrinsic antitumor T-cell responses.. Key Words: Pancreatic ductal adenocarcinoma, tumor microenvironment, ER stress, bone marrow-derived macrophages.