The tumor microenvironment (TME) comprises tumor cells, immune cells, fibroblasts, endothelial cells, mesenchymal stem cells, and non-cellular components such as the extracellular matrix and soluble factors. Through intercellular material exchange and signaling, the TME profoundly influences tumor growth, invasion, metastasis, immune evasion, and therapeutic resistance. Among the diverse forms of intercellular communication within the TME, mitochondrial transfer has garnered increasing attention. Here, we synthesize recent advances in mitochondrial transfer within the TME across three levels: transfer mechanisms, biological consequences, and therapeutic implications. We first outline the principal routes of mitochondrial transfer, including tunneling nanotubes, gap junctions, cell fusion, extracellular vesicles, and free mitochondria. We then examine how mitochondrial transfer contributes to tumor progression, therapeutic resistance, and immune regulation. Finally, we discuss the emerging therapeutic opportunities and potential challenges for clinical translation. Deeper insight into mitochondrial transfer within the TME may provide new opportunities for constraining tumor evolution, overcoming treatment resistance, and developing innovative therapies.

Protein phase separation has emerged as a crucial mechanism for spatiotemporal regulation of intracellular processes, yet its potential to integrate and compute diverse extracellular signals is not fully understood. Here, we show a mechano-biochemical circuit that harnesses phase separation to process mechanical and biochemical inputs, modulating cell fate decisions. We demonstrate that volumetric compression bidirectionally regulates canonical Wnt/β-catenin signaling, where the presence of Wnt ligands determines the locations of AXIN phase separation to form either LRP6 signalosomes on the cell membrane or β-catenin destruction complexes in the cytosol, while the mechanical stimulus promotes degree of phase separation to amplify either the positive or negative signal. This circuit enhances healthy intestinal organoid proliferation while suppressing patient-derived colorectal cancer organoid growth, revealing its potential for precise mechanotherapy. Our findings establish phase separation as a critical component in mechanical signal transduction and provide a framework for integrating mechanical and biochemical cues in cellular decision-making. This approach opens avenues for targeted therapies and deepens our understanding of how cells process complex environmental information.

Hepatocellular carcinoma (HCC) arises within a hypoxic and immunosuppressive tumor microenvironment (TME), where tumor-associated macrophages (TAMs) constitute a major immune population. The impact of hypoxia on TAM functional heterogeneity and their contribution to HCC growth and metastasis remain incompletely understood. We integrated multiple single-cell RNA sequencing datasets and developed a machine learning framework to map cellular hypoxia at single-cell resolution. Hypoxic TAMs (H-TAM) were characterized using transcriptomic and functional assays, including pseudotime trajectory analysis, regulatory network inference, in vitro co-culture, and orthotopic mouse models. Drug sensitivity correlations and in vivo validation were performed to evaluate therapeutic strategies. H-TAM represented the most hypoxic immune population in HCC and exhibited enhanced interactions with malignant hepatocytes. Transcriptomic profiling revealed HIF-1α–dependent hypoxia signaling and upregulation of plasminogen activator, urokinase (uPA, encoded by PLAU). H-TAM-derived uPA engaged its receptor uPAR on HCC cells, promoting epithelial-mesenchymal transition (EMT), migration, invasion, and lung metastasis. In line with this, genetic silencing of the corresponding mouse gene Plau in hypoxia-exposed bone marrow-derived macrophages (H-BMDM) markedly attenuated these pro-tumorigenic effects. Integrative drug sensitivity analysis identified dasatinib as a potential therapeutic agent in HCC with high uPAR expression, and in vivo administration selectively suppressed H-BMDM mediated tumor progression and metastasis while prolonging mouse survival. Hypoxia drives TAM heterogeneity in HCC via an H‑TAM‑intrinsic HIF‑1α–uPA axis that engages uPAR on HCC cells to promote metastasis. uPAR is a potential prognostic biomarker, and dasatinib is a promising therapy to block this axis and improve outcomes.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis with cardiometabolic disorders. Due to the complicated pathophysiological processes, current therapeutic strategies for MASLD remain limited. Previous studies revealed that miR-320 was a regulator of systemic lipid metabolism with multi-targets. However, whether treatments against miR-320 would be benefit to MASLD was unclear. Methods Mice with MASLD were induced by high-fat diet (HFD) treatment. Tough Decoy or sponge against miR-320 was delivered by recombinant adeno-associated virus (serotype 8) vectors in vivo. Hepatic steatosis and plasma lipids were assessed by histopathology, biochemical assays and LC-MS. Moreover, LC-MS, Western blotting, real-time PCR, immunofluorescence and luciferase reporter were performed to investigate the underlying mechanisms. Results Knockdown of miR-320 attenuated HFD-induced MASLD by alleviating hepatic lipid accumulation and hyperlipidemia. Mechanistically, palmitic acid (PA) combined with oleic acid (OA) treatment promoted the translocation of miR-320 from the cytoplasm into the nucleus of hepatocytes. Especially, increased nuclear miR-320 activated the transcription of APOE by targeting its promoter, which in turn aggravated triglyceride accumulation and secretion in hepatocytes. Conclusions Our study revealed that treatments against miR-320 attenuated hepatic steatosis and hyperlipidemia simultaneously, which might be a potential strategy of MASLD.

Hepatocellular carcinoma (HCC) remains a major global malignancy with high incidence and poor survival rates. Etiology-driven metabolic-immune interactions have emerged as a unifying framework for deciphering hepatocarcinogenesis. Hepatitis B virus (HBV) and metabolic dysfunction-associated steatotic liver disease (MASLD) are the two predominant etiological drivers for HCC. Although immunotherapy serves as a cornerstone of HCC treatment, therapeutic response varies considerably across distinct etiologies. Accumulating evidence suggests that etiology-specific dysregulation of lipid metabolism shapes immune imbalance in the tumor microenvironment, thereby accounting for the heterogeneous responses to immunotherapy. Therefore, deciphering etiology-driven metabolic-immune crosstalk may provide new opportunities to improve therapeutic responses. In this review, we propose the framework of etiology-driven metabolic-immune interactions by comparing two major etiologies, HBV and MASLD. Moreover, taking into account the crucial role of lipid metabolism in hepatocarcinogenesis, dietary interventions and lipid metabolism-targeted therapies have also been included so as to offer potential therapeutic strategies.

Protein kinases contribute to hepatocellular carcinoma (HCC) development and immune evasion, posing major challenges for HCC management. Here we show STE20/SPS1-related proline/alanine-rich kinase (SPAK) as a candidate immune exhaustion–associated gene identified through a pooled screen of protein kinases. By integrating bioinformatic analyses, data from patient cohorts, and functional studies in mouse models and cell lines, we demonstrate that elevated expression of SPAK promotes HCC progression, enhances stemness, drives immune exhaustion, and contributes to resistance to targeted therapies. Mechanistically, SPAK phosphorylates GSK3β at Ser9, thereby inhibiting proteasome-mediated degradation of c-Jun and PD-L1. Additionally, we find that DNMT3B-dependent intragenic methylation of SPAK contributes to its high expression in HCC. Notably, the SPAK inhibitor exhibits potent inhibitory effects and synergizes with PD-1 blockade to enhance antitumor efficacy. In summary, these findings establish SPAK as a driver of oncogenesis and immune exhaustion in HCC and highlight dual inhibition as a potential therapeutic strategy. Protein kinases contribute to hepatocellular carcinoma progression and immune evasion. This study identifies SPAK as a key driver of oncogenesis and immune exhaustion, showing that SPAK inhibition synergizes with anti-PD-1 therapy to enhance antitumor efficacy.

Background The complex tumor microenvironment (TME) of colorectal cancer (CRC), composed of diverse cellular components and dynamic interactions, constitutes a major barrier to effective immunotherapy and facilitates disease progression. There is a pressing need to elucidate CRC-intrinsic factors that induce the immunosuppressive TME. Here, we explored the role of homeobox D13 (HOXD13) in shaping the immune microenvironment of CRC and its contribution to immunosuppression.Methods The expression level of HOXD13 was assessed using quantitative real-time PCR, immunoblotting, and immunohistochemistry. The role of HOXD13 in CRC was investigated using orthotopic allograft models and azoxymethane/dextran sulfate sodium-induced spontaneous tumor models in intestine-specific HOXD13 knockout and knock-in mice. The immune landscape of the CRC microenvironment was characterized via flow cytometry and immunofluorescence.Results Our study revealed the upregulation mechanism of HOXD13 in CRC and its functional role in fostering an immunosuppressive TME. HOXD13 was upregulated in CRC, particularly in metastatic cases, and patients exhibiting high HOXD13 expression showed poorer clinical outcomes. Mechanistically, HOXD13 promoted M2-type polarization of tumor-associated macrophages (TAMs) and suppressed CD8+ T cells mediated antitumor immunity by transcriptionally upregulating amphiregulin (AREG) and paired immunoglobulin like type 2 receptor alpha (PILRA) in CRC cells. Concurrently, transforming growth factor beta 1 released from M2-polarized TAMs further augmented HOXD13 expression in CRC cells via activation of the Smad2/3 signaling pathway. This reciprocal interaction formed a self-reinforcing loop that sustained immunosuppression and thereby accelerated tumor progression. Notably, combined inhibition of AREG and programmed cell death ligand 1 effectively disrupted this crosstalk, restored antitumor immunity, and ultimately suppressed CRC progression.Conclusions Our study identified HOXD13 as a pivotal regulator in the establishment of an immunosuppressive TME and suggested that targeting the HOXD13 signaling axis represents a promising strategy to sensitize CRC to immunotherapy.

The fibroblast growth factor (FGF) 15/19-FGF receptor (FGFR) 4 signaling pathway is a crucial endocrine regulatory pathway within the FGF family. The FGF15/19-FGFR4 signaling pathway plays multiple key roles in the liver, involving core physiological processes such as metabolic regulation, bile acid homeostasis maintenance, and hepatocyte proliferation and repair, and is also closely related to the pathogenesis of various liver diseases. At present, targeted therapeutic strategies for the FGF19-FGFR4 signaling axis have shown significant therapeutic potential. Agonists that simulate the physiological functions of FGF19 have been proven to effectively regulate bile acid and lipid metabolism in metabolic diseases and improve liver steatosis and fibrosis. Meanwhile, drugs that selectively inhibit FGFR4 have also demonstrated positive anti-tumor activity in specific tumor types driven by FGF19 overexpression. Given the crucial role of FGF19-FGFR4, clarifying the key mechanisms of this pathway in both physiology and pathology, as well as summarizing targeted therapy, is of vital importance. This review highlights the key role of FGF15/19-FGFR4 signaling in regulating liver physiological functions and reveals how its abnormal expression contributes to the occurrence of benign and malignant liver diseases. In addition, this review points out the potential of FGF15/19-FGFR4 signaling as a biomarker in different liver diseases and briefly discusses the existing treatment strategies for this signaling pathway.

Cancer stem cells (CSCs) are central to tumor progression, metastasis, immune evasion, and therapeutic resistance. Characterized by remarkable self-renewal and adaptability, CSCs can transition dynamically between stem-like and differentiated states in response to external stimuli, a process termed "CSC plasticity." This adaptability underpins their resilience to therapies, including immune checkpoint inhibitors and adoptive cell therapies (ACT). Beyond intrinsic properties, CSCs reside in a specialized microenvironment-the CSC niche-which provides immune-privileged protection, sustains their stemness, and fosters immune suppression. This review highlights the critical role of CSCs and their niche in driving immunotherapy resistance, emphasizing the need for integrative approaches to overcome these challenges.

The overall response rate to immunotherapy is modest in hepatocellular carcinoma (HCC), and immunotherapy resistance mechanisms are incompletely understood. We report that the E3 ubiquitin ligase Riplet is universally silenced by promoter hypermethylation in HCC. Loss of Riplet modulates fatty acid metabolism to promote terminal exhaustion of CD8 T cells. Riplet loss impedes K48-linked polyubiquitination of fatty acid synthase (FASN), consequently accelerating fatty acid production in HCC. Tumor cell-derived free fatty acids, especially palmitic acid (PA/C16:0), activate STAT3 (signal transducers and activators of transcription 3) by enhancing its palmitoylation in T cells, consequently triggering terminal CD8 T cell exhaustion. HCC cells with Riplet deficiency are resistant to anti-PD-1 therapy, and treatment with an FASN inhibitor overcomes resistance. Our study shows how Riplet can alter lipid metabolism and induce CD8 T cell exhaustion and anti-PD-1 resistance, thus suggesting avenues for combined therapies for treating patients with Riplet-deficient HCC.

Lactate, a key metabolite of the Warburg effect, plays a central role in shaping multiple hallmarks of cancer. Through lactate shuttling and engagement with specific receptors, it activates downstream signaling pathways that remodel the tumor microenvironment (TME) and facilitate tumor progression. More recently, lysine lactylation—an emerging post-translational modification derived from lactate—has been identified as a crucial epigenetic mechanism that links altered tumor metabolism with transcriptional regulation. Lactylation has been implicated in promoting tumor proliferation, metastasis, stemness maintenance, immune evasion, and therapeutic resistance across various cancer types. Both tumor and immune cells undergo lactylation, which modulates gene expression and contributes to the immunosuppressive landscape of the TME. Targeting lactate production and transport has shown promise in suppressing tumor growth and enhancing immunotherapeutic efficacy. In this review, we comprehensively discuss the functional roles and underlying mechanisms of lactate and lactylation in cancer progression, with a particular focus on their impact within the TME. We also highlight recent advances in targeting these metabolic processes as potential therapeutic strategies, aiming to provide new perspectives for improving cancer treatment outcomes.

Liver homeostasis is coordinated by crosstalk between resident and infiltrating inflammatory cells. Liver disease creates a dynamic inflammatory microenvironment characterized by aberrant metabolism and continuous hepatic regeneration, making it an important risk factor for hepatocellular carcinoma (HCC) as well as liver failure. Recent studies have revealed a critical heterogeneous population of myeloid-derived suppressor cells (MDSCs), which influence liver disease progression and malignancy by dynamically regulating the immune microenvironment. MDSCs play an important role in preventing excessive immune responses in the liver. However, MDSCs are also associated with the promotion of liver injury and liver cancer progression. The plasticity of MDSCs in liver disease is a unique challenge for therapeutic intervention strategies and requires a deeper understanding of the underlying mechanisms. Here, we review the role of MDSCs in the establishment and progression of liver disease and highlight the evidence for MDSCs as a priority target for current and future therapeutic strategies. We explore the fate of MDSCs from hepatitis to liver cancer, providing recent insights into potential targets for clinical intervention.

The Hippo pathway plays an important role in cell proliferation, differentiation, and cancer occurrence. Yes-associated protein 1 (YAP) is a key effector molecule of Hippo pathway. Previous studies have found abnormal YAP overexpression in many solid tumors, including hepatocellular carcinoma (HCC). Here, we attempt to explore the cancer-promoting mechanism of YAP in HCC. The target gene of Hippo-YAP pathway, Four and a half LIM domain protein 3 (FHL3), was screened by spontaneous hydrodynamic tumor model with YAP participation and two publicly HCC microarray sets. Western blot (WB) and immunohistochemical (IHC) showed high protein levels of FHL3 in tumor tissues and the expression of FHL3 was associated with poorer prognosis. The biological effect experiments showed that FHL3 significantly promoted the progression of HCC. FHL3 interacted with MYC-associated zinc finger protein (MAZ) to recruit MAZ binding to the G-quadruplexes (G4s) structure, which promoted Kirsten rat sarcoma viral oncogene homologue (KRAS) transcription and activation of its downstream signal. Down-regulating KRAS expression inhibited the promoting effect of YAP-FHL3 signaling on HCC. In addition, transactivation of FHL3 mediated by YAP was verified by luciferase reporter assay and chromatin immunoprecipitation (ChIP). FHL3 knockdown inhibited the tumor-promoting effect of YAP and significantly delayed the tumorigenesis and progression caused by YAP. Finally, clinical data validated the correlation between YAP, FHL3, and KRAS expression. In conclusion, we identified a new target of Hippo-YAP signaling, FHL3, which interacts with MAZ to promote KRAS transcription and downstream oncogenic signaling pathway activation, thereby promoting HCC progression.