Editorial: Deciphering cell-cell interactions in triple-negative breast cancer

cancer. Lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as therapeutic targets, it presents a highly aggressive biological profile at diagnosis (1). With higher early distant recurrence rates and poor five-year survival, TNBC stands as a top priority for breakthroughs in precision oncology (2). While extensive studies have explored its molecular subtypes, genetic traits, and signaling pathways, the roots of its invasiveness, immune evasion, and treatment resistance lie in the intricate network of cell-cell interactions (CCIs)(3). Critical evidence shows that even within the same molecular subtype, tumor microenvironment (TME) variations drastically impact prognosis and immunotherapy response, elevating CCIs from a secondary factor to the core of TNBC research(4, 5).TNBC's heterogeneity is reflected not only in dynamic state shifts within tumor cells but also in the multi-layered ecosystem formed by crosstalk between tumor, immune, stromal, and endothelial cells (6,7). Traditional histology and bulk RNA sequencing fail to capture these dynamic relationships, yielding only "averaged" signals that mask contextual details. However, the rapid advancement of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) has transformed the field(8). These technologies enable researchers to penetrate tissue layers, treat 1 cells as interconnected nodes, and their interactions across spatial and temporal axes(9, 10). 2The special issue "Deciphering Cell-Cell Interactions in Cancer" leverages 3 this technological revolution to integrate cutting-edge research, deepen understanding of TNBC 4CCIs, and drive therapeutic innovation. 5Within a single TNBC tumor, multiple molecular subtypes, proliferative states, stem cell 6 populations coexist, while immune-stromal ecosystems exhibit profound complexity. Single-cell 7 spatial omics confirm that cellular composition and function vary drastically across tumor 8 regions (10). Early studies identified a layered spatial architecture: the tumor core, immune 9 exclusion zone, and immune infiltration front (11,12). Each have unique cellular compositions and 10 interaction patterns. Here, tumor-associated macrophages (TAMs), regulatory T cells (Tregs), 11 tumor-associated neutrophils (TANs), and cancer-associated fibroblasts (CAFs) collaborate to 12 suppress anti-tumor immunity via cytokines, chemokines, and metabolic reprogramming (4). 13Response to anti-PD-1/PD-L1 immunotherapy often depends on the spatial arrangement of CD8⁺ 14 T cells, Tregs, myeloid cells, and CAFs, as well as the activity of ligand-receptor axes like 15 CXCL/CXCR and IL1/IL1R (5). Deciphering these tumor-immune-stromal interactions is thus 16 pivotal to improving immunotherapy efficacy. 17 18A review in this issue constructs a comprehensive framework for TNBC immune evasion, 20 Another original study uses integrated single-cell analysis to position TANs as key network nodes 28 and identifies core pro-tumor genes. Functional validation confirms TAN-driven interaction axes 29 as promising therapeutic targets. These findings underscore the multicellular nature of TNBC's 30 immunosuppressive microenvironment and provide new molecular entry points for precision 31 intervention. 32 33The review on scRNA-seq and ST in this issue reveal TNBC CCI complexity stems from both cell 35 type diversity and spatial organization. Spatial analyses show Tregs and M2-TAMs form 36 immunosuppressive "hotspots" in the tumor core, while activated CD8⁺ T cells localize to the 37 periphery. Subsets like ANXA3⁺ epithelial cells suppress T cells via BTLA-TNFRSF14, and the 38 TAM-tumor IL1α-IL1R1 axis drives EMT through positive feedback, enhancing invasion. 39These discoveries illuminate CCI spatial specificity, validating the "structure-signaling-function" 40 causal chain inaccessible to traditional models. Critically, spatial omics enable identification of 41 key nodes driving tumor ecology.From Tissue to Body Fluids: Systemic CCI Signatures 1 TNBC CCIs extend beyond the local TME to generate detectable systemic signatures. A clinical 2 study in this issue introduces the Inflammatory and Immune Index (PIV), derived from 3 peripheral blood neutrophil, monocyte, platelet, and lymphocyte ratios, as a robust prognostic tool post-operative TNBC patients. High PIV correlates with enhanced systemic inflammation and 5 impaired anti-tumor immunity, mirroring the myeloid-predominant, lymphoid-depleted CCI 6 features in the TNBC microenvironment. This highlights the need for CCI research to bridge 7 intra-tissue interactions with accessible biomarkers, enabling non-invasive monitoring of disease 8 and treatment response. 9 10Technical hurdles persist. scRNA-seq batch effects, cell capture biases, and limited sensitivity for 12 rare populations remain unresolved(13). High-resolution ST sacrifices coverage, complicating 13 "whole-tumor + single-cell" analysis, while CCI inference tools (CellPhoneDB, CellChat, 14 NicheNet) yield inconsistent results, requiring robust follow-up validation(14, 15). 15Clinically, most omics studies remain exploratory, with few biomarkers integrated into 16 decision-making. Distinguishing "driver" (targetable) from "passenger" (incidental) CCIs lacks 17 functional validation, and compressing complex CCI atlases into actionable test panels remains 18 unmet. Promisingly, some studies use ST to link spatial gene expression/drug sensitivity gradients 19 to ligand-receptor patterns for treatment prediction (16)(17)(18). In TNBC, researchers are mapping 20 pre-and post-treatment TME remodeling via single-cell/spatial omics to identify response-related 21 CCIs, laying groundwork for personalized therapy (19)(20)(21). 22As technology evolves and interdisciplinary collaborations expand, decoding TNBC CCIs is 23 poised to unlock new therapeutic avenues. Integrating multi-omics, functional validation, and 24 clinical translation will move beyond one-size-fits-all approaches to precision medicine tailored to 25 each patient's unique tumor ecosystem, offering hope for overcoming TNBC's aggressiveness. 26 27 28