Pancreatic cancer (PC) is characterized by a complex tumor microenvironment (TME) and immunosuppressive features that limit the efficacy of existing treatments. Macrophages, particularly tumor-associated macrophages (TAMs), are crucial in pancreatic cancer progression and immune escape. Prolonged exposure to the immunosuppressive TME leads to macrophage exhaustion, reducing their anti-tumor ability and instead promoting tumor growth.
The CSF1/CSF1R signaling pathway is key in macrophage recruitment and functional regulation, making it an effective target for combating macrophage exhaustion. enhances therapeutic efficacy by guiding radiofrequency ablation (RFA) and percutaneous alcohol injection (PEI) in combination with immunomodulators.

Commonly used chemotherapeutic agents such as gemcitabine and FOLFIRINOX have limited their application due to rapid chemoresistance .
TAMs play a crucial role in determining tumor growth, and therapeutic resistance . The CSF1/CSF1R signaling pathway, which modulates TAM functions and behaviors, is vital in regulating the TME. Therefore, targeting the CSF1/CSF1R signaling pathway may represent a promising anti-tumor strategy in the future.

CSF1/CSF1R signaling pathway CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK .

Role of CSF1/CSF1R in TME The CSF1/CSF1R-mediated signaling pathway is critical for the differentiation and recruitment of the mononuclear phagocyte system, particularly macrophages. In TME, activation of the CSF1/CSF1R signaling pathway plays a critical role by promoting the transformation of macrophages to an immunosuppressive phenotype (i.e., M2-type macrophages). These M2-type macrophages inhibit anti-tumor immune responses and promote tumor growth and metastasis by secreting a variety of immunosuppressive factors (e.g., IL-10, TGF-β) and factors that promote tumor angiogenesis (e.g., VEGF). In addition, the CSF1/CSF1R signaling pathway maintains the immunosuppressive state of the TME by regulating the recruitment and survival of TAMs.
CAFs are present in tumors at all stages, are heterogeneous, and their primary function is to synthesize, deposit, and remodel the ECM. However, CAFs also secrete cytokines, chemokines, growth factors, and angiogenic factors.

In the TME, CAFs and TAMs can interact via the CSF1-CSF1R axix. For example, CSF1 expression was positively correlated with the abundance of CSF1R+ CD163+ macrophages in skin cancer patients, which is consistent with a role for CSF1 in mediating macrophage survival. In addition to fibroblasts, tumor cells can also secrete CSF1, suggesting that it may play a pro-tumorigenic role. Consistent with this, in metastatic PDAC, tumor cell-derived CSF1 induces macrophages to produce granulin, a secreted glycoprotein that promotes fibroblast activation and stimulates tumor growth.

Since the presence of CSF1R+ macrophages within tumors correlates with poor survival in various tumor types, targeting CSF1/CSF1R signaling pathway transduction that promotes tumor growth is an attractive strategy to eliminate TAMs, reduce M2 macrophage recruitment, or repolarize them.

Relationship between CSF1/CSF1R and macrophage exhaustion. The CSF1/CSF1R signaling pathway plays an important role in macrophage exhaustion, and its activation induces macrophage exhaustion, causing them to lose their anti-tumor function and instead support tumor growth and immune escape. Studies have shown that macrophage polarization in the TME is highly dependent on the presence of cytokines originating from the tumor cells, from other stromal cells (e.g., immune cells or fibroblasts), and from the local cytokine environment of the macrophages themselves.

Pexidartinib (PLX3397) significantly reduced the number of TAMs and enhanced T-cell-mediated anti-tumor immune responses in multiple tumor models.

For example, Emactuzumab, a monoclonal antibody targeting the CSF1R, has demonstrated potential therapeutic efficacy in a variety of solid tumors.

Several studies are developing bispecific antibodies targeting CSF1R and PD-L1 to enhance therapeutic efficacy by simultaneously inhibiting immunosuppressive signaling and activating immune effects.

Small molecule inhibitors are also effective tools for targeting the CSF1R signaling pathway. These inhibitors block downstream signaling by competing with the ATP-binding site of CSF1R and inhibiting its kinase activity.

For example, Sotuletinib (BLZ945), a potent small molecule inhibitor of CSF1R, has shown the ability to enhance immune responses in a variety of cancer models.

Combining inhibitors of the CSF1/CSF1R signaling pathway with other immunotherapies may further enhance therapeutic effects.

For example, in patients with advanced pancreatic cancer, CSF1R inhibitors in combination with PD-1/PD-L1 inhibitors may simultaneously deregulate immune checkpoint inhibition and reduce the number of immunosuppressive macrophages, thereby enhancing the anti-tumor response of T cells. In addition, CSF1R inhibitors may also be able to be used in combination with chemotherapy, radiotherapy, or other targeted therapies to enhance the tumor cell killing effect.