Cancer research最新文献

MERTK is a receptor tyrosine kinase predominantly expressed on M2 macrophages that plays a critical role in the clearance of apoptotic cells and maintenance of an immune-suppressive phenotype. M2 macrophages are highly abundant in the tumor microenvironment where they facilitate tumor progression and resistance to immunotherapy. MERTK is also overexpressed in cancer cells, where it can drive cancer survival and metastasis through induction of proliferation and anti-apoptotic signaling programs. Here we developed an antibody-drug conjugate (ADC) that simultaneously targets MERTK-expressing M2 tumor associated macrophages and cancer cells. The ADC comprised the monoclonal antibody RGX-019 that binds human MERTK, combined with a monomethyl auristatin E (MMAE) toxic payload. The unconjugated antibody had intrinsic activity to suppress M2 cytokine expression by macrophages, block in vitro colony formation of cancer cells, and inhibit in vivo tumor growth and metastasis. When MMAE was conjugated to the antibody, the ADC exhibited superior in vitro cytotoxicity and in vivo anti-tumor efficacy in MERTK-expressing tumors. Tumor growth inhibition in humanized mice was associated with depletion of tumor-associated M2 macrophages. Furthermore, unlike other MERTK-targeting small molecules or antibodies, no retinal toxicity of RGX-019-MMAE was observed in vivo. These findings reveal that combined therapeutic targeting of MERTK in cancer cells and M2 macrophages offers enhanced opportunities for anti-tumor efficacy in a wide range of MERTK-expressing tumors.

Dedifferentiation programs are commonly enacted during breast cancer progression to enhance tumor cell fitness. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or augmented metastatic potential. In this study, we found that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have thus named this cellular program "immune mimicry." Analysis of public human breast tumor single-cell RNA sequencing datasets and histopathologic breast tumor specimens, as well as functional experiments in vitro in breast cancer cell lines and in vivo in murine transgenic and cell line-derived mammary cancer models, showed that neoplastic cells engaged in immune mimicry. Immune-mimicked neoplastic cells harbored hallmarks of dedifferentiation and were enriched in treatment-resistant and high-grade breast tumors. In aggressive breast cancer cell lines, antiproliferative cytotoxic chemotherapies drove epithelial cells toward immune mimicry. The expression of the CD69 leukocyte activation protein by neoplastic cells conferred a proliferative advantage that facilitated early tumor growth. Together, these findings suggest that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy and that neoplastic immune mimicry has potential clinical utility for patient prognosis and stratification.

Significance: A subset of neoplastic breast epithelial cells express surface receptors canonically attributed to leukocytes and are associated with therapy resistance and aggressive tumor behavior.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stroma that profoundly influences tumor biology and therapeutic response. Cancer-associated fibroblasts (CAF), the major stromal component, exist as heterogeneous populations with both tumor-promoting and tumor-restraining functions. In this issue of Cancer Research, Manoukian and colleagues uncover a previously unrecognized hormonal axis in PDAC, demonstrating that estrogen signaling reprograms fibroblast identity and shapes the tumor microenvironment. Building on prior work identifying an inflammatory CAF subset marked by high OGN and CLEC3B expression (iCAF.1) and associated with favorable prognosis, the authors show that estrogen produced by cancer cells promotes this tumor-restraining phenotype while limiting myofibroblastic CAF activation. Reciprocally, CAF-derived branched-chain amino acids taken up by cancer cells via SLC25A44-mediated uptake fuel estrogen biosynthesis, creating a feedback loop that sustains the classical, less aggressive PDAC subtype. Collectively, these findings establish estrogen as a key modulator of CAF heterogeneity and highlight a novel mechanism of tumor-stroma cross-talk with potential therapeutic implications for stroma-directed interventions in pancreatic cancer. See related article by Manoukian et al., p. 571.

Cancer-associated fibroblasts (CAFs) play a crucial role in shaping the tumor microenvironment (TME) and driving tumor progression. While single-cell transcriptomics has revealed the phenotypic and functional heterogeneity of CAFs, effective therapeutic strategies targeting CAFs remain urgently needed. Here, we identified LRRC15+ CAFs as a tumor-specific CAF subset in lung cancer and proposed LRRC15 as a potential therapeutic target. LRRC15 deficiency suppressed lung cancer progression in mice by modulating macrophage polarization and enhancing CD8+ T cell activation. Mechanistically, LRRC15 deficiency inhibited CD206+ macrophage polarization by reducing extracellular matrix (ECM) production in CAFs, leading to increased CD8+ T cell cytotoxicity. Finally, development of a bispecific antibody targeting LRRC15 and TGF-β enabled effective downregulation of LRRC15 expression in CAFs and limited tumor progression in mice. This study highlights LRRC15 as a promising therapeutic target and provides insights into CAF-directed cancer treatment strategies.

Colorectal cancer (CRC) is characterized by a complex tumor microenvironment (TME) shaped by intestinal microbiota. In this study, 16S rRNA sequencing of CRC patient tissues identified Prevotella, particularly the dominant species Prevotella copri (P. copri), as a key intratumoral bacterium. The parenchymal invasion of P. copri was confirmed by fluorescence in situ hybridization (FISH), and the abundance of P. copri correlated with advanced tumor stages and postoperative serological markers. Notably, the reduced abundance of P. copri in paired normal tissues implied potential bacterial translocation during tumorigenesis. In multiple murine models, P. copri not only accelerated tumor growth but also reprogrammed tumor-associated macrophages (TAMs) toward a pro-tumoral state. Untargeted metabolomics revealed glycerophosphocholine (GPC) as the only conserved metabolite depleted by P. copri across murine models and bacterial cultures, a finding confirmed by spatial metabolomics in clinical specimens. Strikingly, GPC supplementation reprogrammed MARCO+ TAMs toward an anti-tumoral phenotype, effectively counteracting P. copri-mediated tumor progression. Overall, this study uncovers a paradigm in CRC pathogenesis in which P. copri creates an immunosuppressive niche by depleting GPC to manipulate macrophage polarization. These findings position P. copri as both a non-invasive diagnostic marker and druggable therapeutic target, with GPC restoration representing a promising immunometabolic intervention strategy.