Qianming Du

Neutrophils, the most abundant innate immune cells, act as first responders in host defense via phagocytosis, degranulation, ROS production and Neutrophil Extracellular Traps (NETs) formation. Emerging evidence reveals that neutrophils are highly plastic and heterogeneous, acting as critical regulators in tumor biology. Tumor-derived CXCL8 and G-CSF drive emergency granulopoiesis, neutrophil recruitment and functional reprogramming, leading to immune suppression, angiogenesis, matrix remodeling, metastasis and therapy resistance. In specific contexts, neutrophils also exert anti-tumor effects by direct cytotoxicity, enhancing T-cell responses and restricting metastasis, displaying a dual role in cancer. Notably, anti-tumor neutrophils are rare in steady-state tumors but emerge during therapy-induced immune remodeling. Single-cell and spatial multi-omics have challenged the classical N1/N2 dichotomy. Tumor-associated neutrophils (TANs) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are now viewed as overlapping, dynamic populations along a functional continuum, shaped by maturation, metabolism, hypoxia and tissue niches. This review summarizes the dual roles of neutrophils in tumor progression, abnormal granulopoiesis, functional polarization, and revised concepts of TANs and PMN-MDSCs. We highlight NETosis, immune suppression, metabolic reprogramming and therapy resistance, and outline clinical translation including biomarkers (e.g., NLR) and therapeutic strategies. Current challenges and future directions are discussed, aiming to precisely target pro-tumor neutrophils while preserving host antimicrobial immunity.

Carcinoma-associated fibroblasts (CAFs) are core components of the tumor microenvironment, which contribute to tumor initiation and progression through mediating immune suppression. In this study, eight activated CAF subpopulations were identified by single-cell sequencing (scRNA-seq). A specific subtype of CAFs, characterized by PCSK6 expression, strengthened PD-L1 membrane distribution, which contributed to the cytotoxic CD8 ⁺ T cells exhaustion, subsequently promoting the progression of colorectal cancer (CRC). PCSK6 interacting with ACVR1B on CRC cell surface, promoting the acetylation modification of PD-L1 via acetyltransferase p300, followed by strengthened PD-L1 membrane distribution. Loss of PCSK6/ACVR1B signaling in tumor stroma enhanced the intratumoral infiltration and activation of CD8 ⁺ T cells, alleviated growth of CRC and conferred survival advantage in tumor-bearing mice. Moreover, the membrane level of PD-L1 was mediated by the membrane transport complex Rab8/EHBP1L1. Our finding suggested PCSK6/ACVR1B-p300-Rab8/EHBP1L1-PD-L1 signaling axis is significantly activated by CAFs-derived PCSK6, which may offer mechanism interpretation for CAFs mediated CRC immune escape and suggest potential mechanism-based therapeutic strategies for ACVR1B antagonist.

Colorectal cancer (CRC) ranks among the most prevalent malignancies of the digestive system, with the intricate tumor immune microenvironment (TIME) emerging as a key determinant of poor prognosis. Cancer-associated fibroblasts (CAFs), a central constituent of the tumor microenvironment, critically influence tumorigenesis and progression by orchestrating immunosuppression through cytokine secretion and other mechanisms. This study investigates the multifaceted interplay between CAFs and the immune system to identify novel therapeutic targets and improve prognostic outcomes for CRC patients. Through comprehensive analyses of clinical samples and public database data, we identified elevated MFAP2 expression in both CRC tissues and fibroblasts. Mechanistically, we established that CAFs-derived MFAP2 interacts with integrin β8 (ITGB8) on cancer cell surfaces, activating the integrin-FAK-ERK1/2 signaling cascade to drive CRC progression. Furthermore, ERK1/2 phosphorylates and activates the transcription factor ETS2, which upregulates the expression of CYP27A1, an enzyme that modulates lipid metabolism and suppresses CD8 ⁺ T cell function via liver X receptor beta (LXRβ) signaling. These findings elucidate a novel MFAP2-ITGB8-FAK-ERK1/2-ETS2-CYP27A1-LXRβ signaling axis, significantly activated by CAFs-derived MFAP2 in both in vitro and in vivo models, contributing to immune exhaustion and tumor progression. This axis offers significant therapeutic and prognostic potential for CRC, providing critical insights into CAF-mediated immune modulation and paving the way for targeted immunotherapeutic strategies.

Sterile inflammation occurs in various chronic diseases due to many nonmicrobe factors. Examples include endometrial hyperplasia (EH), endometriosis, endometrial cancer, and breast cancer, which are all sterile inflammation diseases induced by estrogen imbalances. However, how estrogen‐induced sterile inflammation regulates EH remains unclear. Here, a single‐cell RNA‐Seq is used to show that SHP2 upregulation in endometrial endothelial cells promotes their inflammatory activation and subsequent transendothelial macrophage migration. Independent of the initial estrogen stimulation, IL1β and TNFα from macrophages then create a feedforward loop that enhances endothelial cell activation and IGF1 secretion. This endothelial cell–macrophage interaction sustains sterile endometrial inflammation and facilitates epithelial cell proliferation, even after estradiol withdrawal. The bulk RNA‐Seq results and phosphoproteomic analysis show that endothelial SHP2 mechanistically enhances RIPK1 activity by dephosphorylating RIPK1^Tyr380. This event activates downstream activator protein 1 (AP‐1) and instigates the inflammation response. Furthermore, targeting SHP2 using SHP099 (an allosteric inhibitor) or endothelial‐specific SHP2 deletion alleviates endothelial cell activation, macrophage infiltration, and EH progression in mice. Collectively, the findings demonstrate that SHP2 mediates the transition of endothelial activation from estradiol‐driven acute inflammation to macrophage‐amplified chronic inflammation. Targeting sterile inflammation mediated by endothelial cell activation is a promising strategy for nonhormonal intervention in estrogen‐related diseases.

This file contains Supplementary Figure S8 and its legend.