1988 INSIGHTS | The Journal of Experimental Medicine Development of pancreatic ductal adenocarcinoma (PDAC) is known to be driven by a persistent inflammatory state, as oncogenic mutations alone are not sufficient for tumorigenesis. Toll-like receptors (TLRs), the pillars of the innate immune system, are highly expressed in the tumor microenvironment and on circulating leukocytes in PDAC. Contrasting results have reported antitumorigenic effects or induction of intrapancreatic inflammation and tumor progression upon ligation of different members of this receptor family. TLR9 in particular is expressed in both tumor and tumor-related cells, and its activation has been shown to impair tumor cell proliferation, suggesting that TLR9 agonists might be useful as adjuvant therapy. In this issue, Zambirinis et al. further examined the specific role of TLR9 signaling in PDAC. Gainand loss-of-function experiments in a mouse model of PDAC showed that TLR9 activation is oncogenic in PDAC. Interestingly, these effects are only partially explained by activation of TLR9 signaling in the tumor cells themselves. Unexpectedly, the authors found expression of TLR9 on pancreatic stellate cells (PSCs; myofibroblast-like cells in the pancreas) and showed that TLR9 activation in these cells results in the production of the CCL3 and CCL11 chemokines. They show for the first time that CCL11 can promote the proliferation of pancreatic cancer cells in a dose-dependent manner. Activation of TLR9 in PSCs also leads to the recruitment of tumor suppressive regulatory T cells (T regs) that, together with TLR9activated myeloid-derived suppressor cells (MDSCs), favor the generation of an immunosuppressive microenvironment. Perhaps one of the most important aspects of the crosstalk between tumor cells and their microenvironment is the inhibition of anticancer immune responses. This new study provides compelling evidence that, in addition to the adaptive immune system, specific molecules in the innate immune system, such as TLR9, can play crucial roles in cancer development. Importantly, the recent development of small molecule agonists and antagonists of TLRs may offer a new strategy to inhibit cancer growth. It will be interesting to determine how such manipulations may be combined with other strategies to activate antitumor T cells. Another exciting aspect of this work is the prominent role of PSCs, providing further support to the notion that desmoplasia from fibroblasts plays a critical role in the recruitment and (in)activation of immune infiltrates in pancreatic cancer. Unquestionably, the molecular complexity of tumor, stroma, and immune cells will continue to engage the efforts of pancreatic cancer researchers for many years to come.