Apoptotic cell overload drives multinucleated giant cell formation after neoadjuvant chemotherapy in colorectal cancer: molecular mechanisms and tumor-suppressive effects.
5 affiliations
- 1Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
- 2Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
- 3Department of Human Anatomy, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
- 4Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China. [email protected].
- 5Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China. [email protected].
Abstract
Colorectal cancer is a common digestive malignancy. Neoadjuvant chemotherapy (NAC) can downstage tumors and increase R0 resection rates. In colorectal cancer specimens with favorable pathological regression after NAC, we observed CD68⁺ multinucleated giant cells (MGCs) preferentially localized in apoptotic cell-rich areas, whereas they were rarely detected in non-NAC specimens. However, the mechanisms driving MGC formation and their functional significance remain unclear. We established an in vitro apoptotic cell-macrophage co-culture system to assess how apoptotic cell burden and efferocytosis regulate macrophage fusion. The TREM2/TYROBP signaling axis was examined using molecular and pharmacological approaches. RNA sequencing, pathway enrichment, lysosome- and metabolism-related transcriptional analyses, and secretory profiling were performed to characterize efferocytosis-induced MGCs. Their effects on colorectal cancer cells and the tumor microenvironment were further evaluated in vitro and in tumor-bearing mouse models. Excessive apoptotic cell burden markedly promoted macrophage fusion and upregulated the fusion-related molecules DCSTAMP/Dcstamp and CDH1/Cdh1. Apoptotic cell overload shifted macrophages from a homeostatic/efferocytic state toward a fusion-prone MGC phenotype. TYROBP/Tyrobp knockdown or loss inhibited macrophage fusion. Mechanistically, apoptotic cell overload activated the TREM2/TYROBP-MAPK/c-FOS-DCSTAMP axis, thereby enhancing DCSTAMP transcription and macrophage fusion. Efferocytosis-induced MGCs showed reduced lysosome-related transcriptional programs and an altered secretory profile, including increased TNF-α expression. Functionally, MGCs inhibited colorectal cancer cell growth in vitro. In tumor-bearing mice, MGCs reduced CD206⁺ macrophage and regulatory T-cell abundance while increasing CD8⁺ T-cell infiltration, thereby contributing to tumor growth suppression. Together, these findings identify efferocytosis-induced MGCs as a distinct macrophage state with altered lysosomal and secretory programs, anti-tumor activity, and the potential to remodel the tumor microenvironment.
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BibTeX
@article{xue2026apoptotic,
title = {{Apoptotic cell overload drives multinucleated giant cell formation after neoadjuvant chemotherapy in colorectal cancer: molecular mechanisms and tumor-suppressive effects.}},
author = {Jiaxin Xue and Zhiwei Wang and Xiaoliang Zhang and Sen Xu and Shuang Wu and Xiaoyue Sun and Meiqi Li and Xueyan Wu and Zhangming Chen and Ming Lu},
journal = {Cell death \& disease},
year = {2026},
month = oct,
doi = {10.1038/s41419-026-09320-w},
url = {https://europepmc.org/article/MED/42919826},
note = {CC BY},
}
RIS
TY - JOUR
TI - Apoptotic cell overload drives multinucleated giant cell formation after neoadjuvant chemotherapy in colorectal cancer: molecular mechanisms and tumor-suppressive effects.
AU - Jiaxin Xue
AU - Zhiwei Wang
AU - Xiaoliang Zhang
AU - Sen Xu
AU - Shuang Wu
AU - Xiaoyue Sun
AU - Meiqi Li
AU - Xueyan Wu
AU - Zhangming Chen
AU - Ming Lu
PY - 2026
DA - 2026/10/05
JO - Cell death & disease
DO - 10.1038/s41419-026-09320-w
UR - https://europepmc.org/article/MED/42919826
AB - Colorectal cancer is a common digestive malignancy. Neoadjuvant chemotherapy (NAC) can downstage tumors and increase R0 resection rates. In colorectal cancer specimens with favorable pathological regression after NAC, we observed CD68⁺ multinucleated giant cells (MGCs) preferentially localized in apoptotic cell-rich areas, whereas they were rarely detected in non-NAC specimens. However, the mechanisms driving MGC formation and their functional significance remain unclear. We established an in vitro apoptotic cell-macrophage co-culture system to assess how apoptotic cell burden and efferocytosis regulate macrophage fusion. The TREM2/TYROBP signaling axis was examined using molecular and pharmacological approaches. RNA sequencing, pathway enrichment, lysosome- and metabolism-related transcriptional analyses, and secretory profiling were performed to characterize efferocytosis-induced MGCs. Their effects on colorectal cancer cells and the tumor microenvironment were further evaluated in vitro and in tumor-bearing mouse models. Excessive apoptotic cell burden markedly promoted macrophage fusion and upregulated the fusion-related molecules DCSTAMP/Dcstamp and CDH1/Cdh1. Apoptotic cell overload shifted macrophages from a homeostatic/efferocytic state toward a fusion-prone MGC phenotype. TYROBP/Tyrobp knockdown or loss inhibited macrophage fusion. Mechanistically, apoptotic cell overload activated the TREM2/TYROBP-MAPK/c-FOS-DCSTAMP axis, thereby enhancing DCSTAMP transcription and macrophage fusion. Efferocytosis-induced MGCs showed reduced lysosome-related transcriptional programs and an altered secretory profile, including increased TNF-α expression. Functionally, MGCs inhibited colorectal cancer cell growth in vitro. In tumor-bearing mice, MGCs reduced CD206⁺ macrophage and regulatory T-cell abundance while increasing CD8⁺ T-cell infiltration, thereby contributing to tumor growth suppression. Together, these findings identify efferocytosis-induced MGCs as a distinct macrophage state with altered lysosomal and secretory programs, anti-tumor activity, and the potential to remodel the tumor microenvironment.
SN - 2041-4889
ER -