Integrin α2β1, a major collagen-binding receptor, functions as a key mediator of cell-extracellular matrix (ECM) communication, mechanosensing, and adhesion-dependent signaling. As a core molecular switch in cancer biology, integrin α2 profoundly influences the metastatic cascade—from local invasion, intravasation, survival in circulation, and pre-metastatic niche formation to dormancy and colonization. Although extensive studies indicate that integrin α2β1 regulates tumor proliferation, migration, ECM remodeling, angiogenesis, and immune modulation, its mechanochemical activation mechanisms and context-dependent functions across different stages of metastasis remain incompletely defined. This review systematically summarizes the structural characteristics, activation mechanisms, regulatory networks, and functional roles of integrin α2β1 in the cancer metastatic cascade. We first describe the domain architecture of integrin α2, emphasizing the structural determinants underlying ligand specificity and metal ion-dependent adhesion. We then outline multi-level regulatory mechanisms that drive variable integrin α2 expression across tumor types. The dual biochemical and mechanical modes of integrin α2β1 activation are discussed, with emphasis on nanocluster formation, focal adhesion maturation, force-dependent conformational changes, and key downstream signaling pathways. We further dissect the stage-specific contributions of integrin α2β1 at each stage of metastasis, including its contributions to epithelial-mesenchymal transition, matrix metalloproteinase - mediated ECM degradation, vascular remodeling, circulating tumor cell survival, immune evasion, pre-metastatic niche formation, tumor dormancy, and organotropic colonization. Finally, we review current progress in integrin α2-targeted therapies—including small-molecule inhibitors, monoclonal antibodies, natural compounds, and nanomedicine-based delivery systems—and discuss future directions that leverage mechanobiology, integrin-targeted biomaterials, and computational drug design. Integrin α2β1 is a central mechanochemical regulator of the metastatic cascade, coordinating tumor cell responses to extracellular and intracellular cues. Its functions span critical metastatic processes, making integrin α2 and its downstream pathways promising therapeutic targets. Continued advances in mechanobiology and multi-omics technologies will be essential to refine integrin-centered strategies and improve interventions against metastatic cancer.

BACKGROUND:Breast cancer is the most common malignant tumor in women. Human epidermal growth factor receptor 2 (HER2) is a key biomarker for classification and treatment. A subgroup with HER2-low expression has been identified, but existing evidence is heterogeneous. This systematic review and meta-analysis compared pathological response and survival outcomes between HER2-low and HER2-zero early-stage breast cancer to clarify prognostic features. METHODS:This study followed PRISMA guidelines and was registered in PROSPERO (CRD420251120506). PubMed, Embase, Web of Science, ClinicalTrials.gov, and major oncology conferences were searched through September 2025. Cohort studies of early-stage breast cancer comparing HER2-low (IHC 1+/2+ and ISH-negative) vs. HER2-zero with extractable pCR, DFS, or OS data were included. Studies involving HER2-positive patients or inconsistent definitions were excluded. Meta-analyses were performed using RevMan 5.3. RESULTS:Twenty-eight studies involving 115,182 patients were included. HER2-low patients showed significantly lower pCR rates (OR = 0.58, 95% CI: 0.52-0.65). DFS favored HER2-low (multivariate HR = 0.75, 95% CI: 0.69-0.83), especially in HR+ tumors, with a weaker effect in HR- cases. OS also favored HER2-low (HR = 0.80, 95% CI: 0.72-0.89), mainly driven by the HR- subgroup; no OS difference was seen in HR+ tumors. Sensitivity analyses and funnel plots indicated robust results with no apparent publication bias. Overall study quality was high (17 high-quality, 11 moderate-quality). CONCLUSION:HER2-low early breast cancer shows lower pCR after neoadjuvant therapy but better long-term survival. These findings support the clinical relevance of HER2-low as a biologically meaningful subgroup within HER2-negative disease, while its status as a stable and independent subtype still requires further validation through prospective studies, standardized testing, and multi-omics investigation.

Therapeutic resistance remains a major cause of treatment failure and disease recurrence across cancer types, considerably limiting the long-term efficacy of chemotherapies, targeted therapies, and immunotherapies. Growing evidence indicates that resistance cannot be fully explained by static genetic alterations but rather arises from dynamic and reversible adaptive processes. Epigenetic regulation governs transcriptional plasticity, cellular state transitions, and tumor heterogeneity under therapeutic stress. Alterations in DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA networks enable cancer cells to silence tumor suppressor programs, activate compensatory survival pathways, acquire stem cell-like drug-tolerant persister states, and remodel the tumor immune microenvironment. These mechanisms often act in a coordinated manner to form a dynamic regulatory system that supports adaptive resistance. However, current studies have frequently focused on individual epigenetic regulators and have lacked an integrated framework to explain how epigenetic plasticity collectively drives therapeutic resistance. In this review, we deconstruct cancer therapy resistance using the conceptual framework of the “epigenetic landscape.” We summarize the molecular functions and crosstalk among the major epigenetic layers and describe how this integrated network sustains key resistance-associated phenotypes. We also discuss emerging therapeutic strategies that target epigenetic plasticity, including epigenetic drugs, targeted protein degradation, epigenetic editing, and rational combination therapies. Overall, this review provides a systematic framework for understanding epigenetically mediated therapy resistance and highlights epigenetic plasticity as a therapeutic vulnerability for developing durable cancer treatments.

T cell exhaustion represents a pivotal mechanism of immune escape in cancer, with its inherent heterogeneity and dynamic plasticity being key determinants of the variable responses and resistance to immune checkpoint inhibitors (ICIs). This review comprehensively delineates the multifaceted heterogeneity of exhausted T (TEX) cells, tracing their developmental trajectory from precursor exhausted T (TPEX) cells to terminally differentiated exhausted T (TEX -term) cells. We highlight both distinct and shared exhaustion features across diverse cancer types and spatial niches within the tumor microenvironment. Furthermore, we examine the multi-layer biomarkers that drive and define this state, including characteristic surface inhibitory receptors, core transcription factors, and metabolism-associated molecules. Grounded in this mechanistic understanding, we discuss emerging therapeutic strategies aimed at reversing T cell exhaustion. These range from the optimized application of ICIs and rational combination therapies involving epigenetic or metabolic interventions, to next-generation engineered cell therapies such as chimeric antigen receptor T cell (CAR-T), T cell receptor-engineered T cell (TCR-T), and tumor-infiltrating lymphocytes (TILs), alongside emerging modalities including oncolytic viruses and bispecific antibodies. Finally, we discuss prevailing challenges and future directions, emphasizing that deciphering the heterogeneous landscape of TEX cells, identifying precise biomarkers, and developing temporally controlled combination regimens are imperative to effectively reverse T cell exhaustion and broaden the therapeutic efficacy of cancer immunotherapy.

Aberrant lysine acetylation modifications driven epigenetic dysregulation of gene expression represents a central mechanism underlying high relapse rates and drug resistance in hematologic malignancies. Developing novel therapeutic strategies that target chromatin homeostasis and gene regulatory networks is thus critical to overcoming current clinical challenges. Polyphenolic compounds are a class of natural phytochemicals characterized by phenolic hydroxyl groups that include candidate lysine acetylation modulators showing promise for intervention in hematologic malignancies because of their multi-target synergistic mechanisms and favorable toxicity profiles. These compounds dynamically modulate the activities of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), orchestrating epigenetic reprogramming that significantly reduces the incidence of drug resistance with low risk of off-target toxicity. This review comprehensively synthesizes our current understanding of polyphenol-mediated acetylation regulation and delineates their unique therapeutic advantages in hematologic malignancy treatment. By systematically mining multidimensional mechanistic data from the literature describing polyphenol-driven acetylation remodeling, we have established structure–activity relationships (SARs) correlating polyphenolic scaffolds with acetylation modulation, with the goal of elucidating specific structural advantages in epigenetic targeting from a medicinal chemistry perspective. We also investigated an innovative targeted delivery paradigm leveraging integrated nanotechnology platforms, which may advance precision delivery of polyphenolic compounds and provide novel strategies and new directions for anti-hematologic malignancy drug development.

Background: Lactylation is a novel form of post-translational modification. The role of lactylation in breast cancer (BRCA), especially its interplay with immune response and metabolism, remains to be explored. This study utilized bioinformatics analysis to identify genes related to lactate production and preliminarily explored their roles in BRCA. Methods: Using data from The Cancer Genome Atlas database (TCGA) and dataset GSE20685, we analyzed the expression and mutation patterns of lactylation-related genes (LRGs). Unsupervised clustering was performed to screen lactylation-related clusters. We further investigated the presence, functional location, and association with BRCA of global lactylation. Following Cox regression and LASSO regression analyses, a LRG model was developed and validated. Subsequently, the associations of LRGs-based risk model with clinical features, immunotherapy responses, immune cell infiltration, mutation landscape, and biological functions were explored. Single-cell expression levels of core genes were also determined. Finally, the functional role of the core gene was validated through in vitro assays (MTT, colony formation, Transwell) and in vivo xenograft models. Results: An elevation of global lactylation was observed, particularly in malignant tumors such as BRCA. Thereafter, a 4-LRG risk model was developed for predicting the prognosis of BRCA. High-and low-risk BRCA groups exhibited significant differences in biological functions, checkpoint expressions, immune cell infiltrations, immunotherapy responses, drug sensitivities, and clinical features. Further analysis revealed that DDX21 was widely expressed in various cell types of BRCA, indicating a potential role in immunity regulation in BRCA. In addition, silencing DDX21 can inhibit the growth of BRCA cells in vitro and xenograft tumor growth in vivo. Conclusions: We developed a lactylation-related prognostic model and identified DDX21 as a key oncogenic driver and potential therapeutic target in BRCA. However, the lack of clinical research on DDX21 is the main limitation of this study.

BACKGROUND:Triple-negative breast cancer (TNBC) is characterized by a high propensity for metastatic relapse and a robust infiltration of tumor-associated macrophages (TAMs), which orchestrate a pro-metastatic microenvironment. Hedyotis diffusa Willd-Scutellaria barbata (HS), a classical herbal pair, exhibits potent antitumor activities; however, its specific role in modulating TAM-dependent metastasis remains unclear. PURPOSE:This study investigated whether HS suppresses TNBC metastasis by modulating the functional state of TAMs, and sought to define the bioactive constituents and their molecular targets. METHODS:The anti-metastatic activity of HS was assessed in a 4T1-luc orthotopic tumor model and a non-contact co-culture system. Macrophage depletion with clodronate liposomes was used to assess the contribution of macrophages to HS efficacy. Single-cell RNA sequencing analysis was performed to characterize macrophage-tumor cell communication. High-resolution LC-MS, molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assays (CETSA) were integrated to identify HS derived constituents and validate their target engagement. RESULTS:HS reduced orthotopic tumor growth and distant metastatic burden in vivo. HS also reduced F4/80 positive macrophage accumulation and CD206 positive TAM associated signals in tumor tissues, and suppressed IL-4/IL-13 induced macrophage polarization in vitro. In co-culture models, HS pretreated macrophages showed a reduced ability to promote TNBC cell migration, invasion, epithelial-mesenchymal transition, and clonogenic growth. Macrophage depletion attenuated the antitumor effects of HS and apigenin (API), supporting a macrophage-dependent mechanism. Single-cell analysis identified macrophage-associated OPN and its interaction with tumor-cell CD44 as a candidate paracrine signaling axis. HS reduced macrophage OPN expression and attenuated CD44-MEK/ERK signaling in TNBC cells. API was identified as an OPN-binding constituent of HS and disrupted macrophage-derived OPN-mediated CD44-MEK/ERK activation. In vivo, API suppressed orthotopic tumor growth and reduced lung metastatic lesions. CONCLUSION:This study demonstrates that the HS herbal pair suppresses TNBC metastasis by remodeling the macrophage functional state and disrupting the signaling axis between OPN and CD44 driven by TAMs. The identification of API as an OPN binding constituent provides a mechanistic basis for further investigation of compounds derived from HS that target macrophage-tumor crosstalk in TNBC.

ABSTRACT Cancer metastasis is the leading cause of cancer‐related mortality, involving complex interactions between tumor cells and the mechanically heterogeneous tumor microenvironment. The cell nucleus serves as a central mechanosensor in metastasis, dynamically perceiving and responding to the spatiotemporal evolution of mechanical signals throughout the metastatic cascade. These mechanical responses, such as nuclear deformation, nuclear envelope rupture and repair, and chromatin remodeling, not only directly regulate cellular behavior but also transduce biochemical signals through mechanotransduction pathways. While studies have focused on nuclear softening, membrane rupture/repair, and mechanical memory in metastasis, a comprehensive integration of the nucleus's spatiotemporal mechanical responses across the entire metastatic process is lacking. This review proposes a “nucleus‐centered cross‐stage mechanical signal decoding” framework, highlighting how nuclear mechanosensitive components dynamically decode mechanical signals in response to changes in metastatic stages and microenvironmental features. We further explore innovative anti‐metastasis strategies targeting key nuclear mechanosensitive elements and downstream transcriptional regulators, evaluating the therapeutic potential of physical interventions at specific metastatic stages. Additionally, we discuss ongoing controversies in the field, offering a novel perspective for understanding metastasis and developing integrated therapeutic paradigms.

Triple-negative breast cancer (TNBC) remains a major clinical challenge due to its aggressive nature and limited therapeutic options. Among emerging therapeutic approaches, ferroptosis induction has attracted increasing attention due to its unique mode of action; however, its efficacy is often restricted by insufficient intratumoral drug accumulation and the abnormal tumor vascular microenvironment. Here, we designed a CREKA-modified peptide, Pep1, to actively target tumor-associated fibrin and increase accumulation in the tumor and further developed a pH-responsive self-assembling nanoplatform, PS/Pep1. PS/Pep1 significantly improved intratumoral drug bioavailability, promoted lipid peroxidation, suppressed glutathione peroxidase 4 (GPX4) activity, and downregulated vascular endothelial growth factor (VEGF) expression, thereby inducing ferroptosis- and apoptosis-mediated tumor cell death while suppressing angiogenesis. Upon exposure to the acidic tumor microenvironment, PS/Pep1 transformed from spherical nanoparticles into aggregates with high aspect ratios, facilitating deep tumor penetration and sustained local retention. In summary, this study presents a smart nanomedicine strategy that integrates active targeting, microenvironment-responsive structural transformation, and the synergistic regulation of ferroptosis-mediated cell death and angiogenesis, providing a promising therapeutic paradigm for TNBC treatment.

Drug resistance (MDR) poses a significant challenge in breast cancer (BrCa) treatment, resulting in reduced efficacy and increased tumor recurrence. Resolving MDR in BrCa is necessary for improving the clinical efficacy of antitumor therapy. However, the molecular mechanisms underlying MDR are complex and involve various biological processes, including ABC drug transporter-mediated drug efflux, abnormal drug metabolism, and the development of the tumor microenvironment. The abnormal expression of ABC transporter proteins constitutes a critical mechanism driving MDR in BrCa. Factors like breast cancer stem cells (BCSCs), epigenetic changes, cell membrane lipids, and microenvironmental components affect the expression and function of ABC transporter proteins in BrCa. Here, we focus on the roles of Pglycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP) in relation to MDR. Additionally, we review the factors affecting the expression and function of these transporters, emphasizing strategies such as gene modification, drug development, and modulation of cell membrane lipids.

Background:Non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer cases. Further, the complex tumor immune microenvironment (TIME) is a critical factor in treatment resistance and poor prognosis associated with tumors. Tumor-associated macrophages (TAMs), a major component of the TIME, significantly promote tumor progression through their polarization toward the immunosuppressive M2 phenotype. Reportedly, NSCLC cells regulate TAM polarization by secreting extracellular vesicles (EVs) to deliver miRNAs; however, the specific underlying molecular mechanisms remain unclear. In this study, we aimed to elucidate the regulatory role of miRNAs derived from NSCLC EVs in TAM polarization and explore potential novel therapeutic targets. Methods:Through high-throughput sequencing and bioinformatics analysis, key regulatory targets were screened. Ki-67 staining was employed to detect cell proliferation, flow cytometry was performed to analyze cell apoptosis, RT-qPCR and Western blot were used to measure mRNA and protein expression levels, and Transwell assays were conducted to assess cell migration and invasion capabilities to investigate the molecular mechanisms underlying the miRNA-mediated regulation of TAM polarization by NSCLC-derived EVs. Results:NSCLC-derived EVs were successfully isolated and characterized. Bioinformatics analysis of EVs' miRNA sequencing data revealed that the hsa-let-7b-5p/Adaptor-Related Protein Complex 1 subunit sigma 1 (AP1S1) axis may be a key regulator of TAM polarization. In vitro experiments confirmed that the hsa-let-7b-5p mimic potentially suppressed M2 polarization of TAMs via the AP1S1/p53 signaling axis, thereby attenuating the proliferation, migration, and invasion capabilities of NSCLC cells. Conclusion:This study revealed the molecular mechanism by which hsa-let-7b-5p reshapes the immune microenvironment of NSCLC cells by targeting and inhibiting AP1S1 expression, thereby regulating the polarization of TAMs toward the M2 phenotype. Thus, the hsa-let-7b-5p/AP1S1 axis may serve as a potential therapeutic target for NSCLC immunotherapy, providing novel strategies for improving patient prognosis.

Recently evidence has suggested that long non-coding RNAs (lncRNAs) play a pivotal role in the prognosis and treatment of leukemia. However, studies on their use in differentiation therapy of acute myeloid leukemia (AML) remain scarce. In this study, we found that AC098613.1 was significantly increased in differentiated THP-1 cells, while its expression was significantly lower in AML patients. Moreover, AC098613.1 overexpression inhibited proliferation and induced differentiation of THP-1 and HL-60 cells. Mechanistically, we found that AC098613.1 targeted cell division cycle 5-like protein (CDC5L) to increase its stability, thereby enhancing its abundance and nuclear localization, and promoted the transcription of ADP-ribosylation factor GTPase activating protein with dual PH domains 1 (ADAP1) and the expression of nardilysin (encoded by NRD1), which ultimately induced the differentiation of AML cells. We further demonstrated in vivo that AC098613.1 overexpression significantly inhibited tumor growth by affecting the stability of CDC5L and regulating the expression of ADAP1, NRD1 and cyclin-dependent kinase 1 (CDK1). The research demonstrates that AC098613.1 promotes AML cell differentiation by regulating the CDC5L/ADAP1/NRD1 axis, providing a new target for AML differentiation therapy.

T cell exhaustion has traditionally been defined as a state of progressive functional impairment and specific epigenetic remodeling induced by chronic antigen stimulation. However, emerging multidisciplinary evidence indicates that exhaustion is not merely a terminal stage of functional failure; rather, it represents an evolutionarily conserved adaptive program designed to balance long-term immune surveillance with the limitation of excessive pathological damage. This review focuses on the positive regulatory roles of T cell exhaustion within the tumor microenvironment. It elucidates how the exhausted state avoids lethal inflammation by restraining excessive activation while preserving a durable progenitor pool, thereby ultimately establishing a homeostatic balance between sustained tumor control and host survival. Overall, a comprehensive understanding of the evolutionary principles underlying this adaptive program provides important guidance for the design of precision immunotherapies that balance efficacy and safety. Strategically targeting and harnessing these protective features may greatly optimize the clinical benefits of solid tumor treatment and guide the development of next-generation innovative immunotherapies.

BACKGROUND:Epidemiological data show that approximately 80% of cancer patients experience pain of varying degrees throughout the course of their disease, with nearly one-third experiencing severe pain, significantly impacting their quality of life and the effectiveness of antitumor treatment. Triple-negative (TN) breast cancer tissues typically exhibit increased stromal stiffness and abnormally elevated mechanical stress; these biomechanical alterations may amplify pain signals by activating mechanosensitive channels. Utilizing single-cell RNA sequencing analysis, this study aims to elucidate the potential biological links between fibroblast mechanotransduction and cancer-associated pain, thereby providing a theoretical basis for clinical diagnosis and treatment. METHODS:Dimensionality reduction and unsupervised clustering were used to identify cell types in TN breast cancer single-cell RNA sequencing data. To assess the association between pain and mechanical stimulation, we constructed a set of gene signatures associated with mechanical stimulation and pain and calculated scores using the Area Under the Curve Cell (AUCell). CellChat and SCENIC were used to reveal the communication networks and transcription factor regulatory mechanisms of fibroblast subtypes. RESULTS:COL3A1+ fibroblasts derived from TN breast cancer are highly involved in biological processes such as extracellular matrix remodeling, collagen fiber formation, and mechanotransduction. To assess the association between pain and mechanical stimulation, we constructed a gene signature set related to mechanical stimuli and pain and calculated corresponding scores using the AUCell tool. Cell communication studies showed that COL3A1+ fibroblasts interact extensively with epithelial cells and other cells through laminin and collagen signaling pathways, potentially leading to mechanotransduction remodeling of the TN breast cancer microenvironment. CONCLUSION:COL3A1+ fibroblasts demonstrate enhanced transcriptional profiles pertinent to collagen deposition and cytoskeletal reorganization, which are correlated with mechanotransduction signaling and may be connected with mechanical sensitivity in cancer-related pain. This study systematically characterizes the potential relationship between fibroblast-associated mechanotransduction characteristics and pain-related gene signatures at the single-cell level in TN breast cancer. These findings offer hypothesis-generating insights into the molecular landscape of tumor-associated pain, although additional experimental and clinical validation is necessary.

CD8⁺ T-cell exhaustion is a distinct differentiation state driven by persistent antigen stimulation, and its establishment and maintenance are major barriers to effective cancer immunotherapy. Although the transcriptional and epigenetic landscapes of exhausted CD8⁺ T cells have been extensively characterized, it remains unclear how sustained external stimulation is integrated at the level of protein function to produce stable dysfunction and altered cell fate. Post-translational modifications constitute a key regulatory layer of protein function. They form a dynamic network that links persistent antigenic stimulation and tumor microenvironmental stress to cell fate, and therefore provide a critical entry point for understanding how exhaustion is initiated and maintained. In this review, we focus on how post-translational modifications convert persistent antigen stimulation and tumor microenvironmental stress into protein-level dysregulation and ultimately lock CD8⁺ T cells into an exhausted fate. We summarize how multiple classes of post-translational modifications drive exhaustion through effects on signal transduction, protein homeostasis, metabolic stress responses, and epigenetic reprogramming. We then discuss potential intervention strategies centered on critical regulatory nodes that may preserve the plasticity of precursor exhausted CD8⁺ T cells, restrain stabilization of the terminally exhausted state in CD8⁺ T cells, and optimize rational combination therapies. Finally, we outline the translational challenges and future directions of targeting post-translational modifications, and emphasize that identifying actionable modification nodes will be important for patient stratification and combination design in cancer immunotherapy.

Immune checkpoint blockade has shown benefit in some Triple-negative breast cancer (TNBC) patients, but responses are variable. BRCA1-mutated TNBC represents a biologically distinct subgroup, potentially differing in immunogenicity and immunotherapy responsiveness. However, immune microenvironment differences between BRCA1-mutated and sporadic TNBC remain incompletely understood. By performing single-cell RNA sequencing analysis on sporadic TNBC and BRCA1 mutant TNBC, we assessed immune cell composition, transcriptional program, pathways, stemness, differentiation, and transcription factor regulatory networks. B cell and plasma cell subtypes were further explored using AUCell, CytoTRACE, Monocle2, and Slingshot. Compared to sporadic TNBC, BRCA1-mutated TNBC exhibited a distinct immune landscape with enriched naïve and memory B cells, while sporadic TNBC was dominated by terminally differentiated plasma cells, including IgA plasma cells. Functional enrichment analyses showed enhanced adaptive immune signaling, antigen presentation, and B cell receptor pathways in BRCA1-mutated TNBC, while sporadic TNBC had humoral effector and immunoregulatory programs. Trajectory and stemness analyses indicated enhanced cellular plasticity and decreased differentiation in B cells derived from BRCA1-mutated triple-negative breast cancer. Analysis of transcription factors revealed JUND and ETV1 in BRCA1-mutated TNBC, and MEIS1 and CEBPB in sporadic TNBC. Our findings underscore disparities in the immune ecosystem between BRCA1-mutated and spontaneous TNBC, indicating that the B cell-centric immunological milieu in BRCA1-mutated TNBC may offer a more advantageous setting for immunotherapy. Sporadic TNBC, by contrast, exhibits an immunological state characterized by plasma cells, which may restrict immune reactivation. These data indicate that B cell-based immunological stratification may guide precision immunotherapy approaches.

Tumor-associated macrophages (TAMs) play a critical role in the immunosuppressive tumor microenvironment (TME). Although the biochemical signaling pathways regulating TAMs have been extensively elucidated, how these cells persistently sense physical properties of the tumor stroma—such as matrix stiffness, tension, and compression—and translate them into sustained immunosuppressive programs remains to be systematically addressed. Unlike other infiltrating immune cell populations that primarily engage in transient adhesive interactions, TAMs utilize integrins for stable spatial anchoring and continuous mechanotransduction. In this review, we synthesize current evidence on the integrin-TAM mechanosensing axis. We first distinguish the persistent mechanobiological features of TAMs from those of structural stromal cells and other transiently infiltrating lymphocytes. Subsequently, we delineate how force-dependent signaling shapes TAM phenotypic plasticity, metabolic reprogramming, and spatial organization. Crucially, we define a self-amplifying biomechanical-immune feedback framework, demonstrating how mechanically remodeled TAMs actively exacerbate extracellular matrix stiffening to consolidate the immunosuppressive niche. Furthermore, we critically evaluate the translational relevance of this axis, analyzing the limitations of past single-target integrin inhibitors and highlighting the emerging potential of multidimensional combination therapeutic strategies. Targeting integrin-dependent mechanotransduction provides a rational, system-level strategy to dismantle mechanically reinforced immune barriers. Breaking this interlocking feedback framework offers new insights for remodeling the TME and enhancing the efficacy of current immunotherapies. Highlights integrin-mediated mechanotransduction linking biomechanics to immunity. Illustrates how mechanical cues reshape macrophage immunoregulatory programs. Discusses integrin-macrophage-ECM interactions in immunosuppressive niches. Outlines therapeutic strategies targeting integrin-dependent mechanotransduction.

T cell exhaustion represents a major barrier to the efficacy of cancer immunotherapy, driven by complex transcriptional reprogramming, epigenetic remodeling, and metabolic imbalance. Cheng et al. report in Nature that the E3 ubiquitin ligase Kelch-like protein 6 (KLHL6) dually suppresses T cell exhaustion and mitochondrial dysfunction via proteostasis control, establishing a new therapeutic target.

The progression and therapeutic resistance of solid tumors are profoundly influenced by the mechanical microenvironment, in which extracellular matrix stiffening, elevated interstitial pressure, and aberrant mechanotransductive signaling constitute critical physical barriers. Tumor-associated macrophages (TAMs) occupy a central position in this process. They not only act as active architects that remodel the matrix and exacerbate fibrosis, but their phenotypes and functions are also reciprocally regulated by the mechanical microenvironment, thereby forming a self-reinforcing malignant loop. Accordingly, targeting TAMs to mechanically soften tumors has emerged as an important therapeutic strategy, encompassing TAMs depletion, reprogramming, inhibition of TAM-mediated the extracellular matrix (ECM) modification, and disruption of mechanosensing pathways. In addition, mechanical immunoengineering and combination therapeutic strategies provide new tools for modulating the tumor mechanical-immune microenvironment. This review systematically examines the bidirectional regulatory mechanisms of TAMs within the mechanical microenvironment and the corresponding therapeutic strategies, and highlights that overcoming spatiotemporal heterogeneity and developing precision intervention paradigms are key to achieving future clinical translation.