Tumor-associated tissue-resident macrophages drive pancreatic cancer progression through IGF1-IGF1R signaling

Yamamoto, Y.; Takeuchi, K.; Tabe, S.; Okumura, A.; Aoshima, K.; Eto, R.; Konishi, T.; Yamamoto, N.; Miyagi, Y.; Ohtsuka, M.; Tanimizu, N.; Taniguchi, H.

doi:10.64898/2026.05.08.723679

bioRxiv · 10.64898/2026.05.08.723679

Tumor-associated tissue-resident macrophages drive pancreatic cancer progression through IGF1-IGF1R signaling

Yamamoto, Y.·Takeuchi, K.·Tabe, S.·Okumura, A.·Aoshima, K.·Eto, R.·Konishi, T.·Yamamoto, N.·Miyagi, Y.·Ohtsuka, M.·Tanimizu, N.·Taniguchi, H.

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Abstract

The specific contribution of tissue-resident macrophages (TRMs) to pancreatic ductal adenocarcinoma (PDAC) progression remains unclear. Here, we found that a high abundance of TRM-derived tumor-associated macrophages (TRM-TAMs) is an independent indicator of poor prognosis in patients with PDAC. To elucidate the underlying mechanism, we established an advanced organoid platform (iMac-FPCO), which incorporates macrophages derived from human induced pluripotent stem cells to reflect the differentiation process of TRMs. Single-cell transcriptomic analysis revealed this model recapitulates the transcriptional identity of TRM-TAMs in patient tissue. We demonstrated that TRM-TAMs drive cancer cell proliferation, while maintaining chemoresistance, and identified TRM-derived insulin-like growth factor 1 (IGF1) as the critical mediator. This result provides a rationale for why previous trials targeting IGF1 receptor (IGF1R) failed to improve survival in unselected patient populations. We hypothesize that stratifying patients by TRM-TAM abundance could help identify a responsive subgroup, thereby reviving IGF1R-targeted therapy as a viable treatment for PDAC.

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Yamamoto, Y., Takeuchi, K., Tabe, S., Okumura, A., Aoshima, K., Eto, R., Konishi, T., Yamamoto, N., Miyagi, Y., Ohtsuka, M., Tanimizu, N., Taniguchi, H.. 2026-05-12. Tumor-associated tissue-resident macrophages drive pancreatic cancer progression through IGF1-IGF1R signaling. https://doi.org/10.64898/2026.05.08.723679

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