Tumor-associated macrophages (TAMs), especially SPP1⁺TAMs are associated with poor prognosis of colorectal cancer (CRC). However, the underlying mechanism remains unclear, and the therapeutic targets have yet to be identified.

Single-cell RNA sequencing (scRNA-seq) data were used to explore the interactions between SPP1⁺TAMs and CRC cells. TAM co-culture model, liver metastasis models and clinical tissue microarray (n=42) were used to validate the key secreted cellular factor and its associated receptor that mediated the interactions between SPP1⁺TAMs and CRC cells.

We found that migration inhibitory factor (MIF) was the most important signaling molecule involved in the interaction between SPP1⁺TAMs and CRC cells, as revealed by cellular interaction analysis of integrated scRNA-seq datasets. Interestingly, SPP1 was co-expressed with MIF receptor CD44 on SPP1⁺TAMs. When SPP1⁺TAMs was activated, CD44 was crucial for MIF-mediated angiogenesis. Our data showed that CRC cells activated SPP1⁺TAMs, which was abolished by blocking the MIF signaling both in vitro and in vivo. Furthermore, the pathological role of MIF is suggested by the elevated expression of MIF and activation of SPP1⁺TAMs in CRC patients, as demonstrated in clinical tissue microarray. Further mechanistic studies revealed that POU2F2 was a crucial transcription factor mediating MIF-driven activation of SPP1⁺TAMs, and that BCL9L was a direct downstream target of POU2F2.

Our findings suggest that the MIF/CD44/POU2F2/BCL9L signaling axis is involved in the proangiogenic capacity of activated SPP1⁺TAMs, thereby enhances CRC metastasis. Targeting this novel signaling axis can effectively suppress the SPP1⁺TAM activation, which represents a promising and pivotal strategy for managing CRC metastasis.

The spleen is the largest secondary lymphoid organ in humans. Beyond its classical role in clearance of senescent erythrocytes, it functions as a pivotal node in systemic immune surveillance. Emerging evidence indicates that tumor can remotely remodel splenic niches through a spectrum of soluble mediators, thereby accelerating tumor initiation and progression. Tumor-derived signals divert splenic hematopoietic stem and progenitor cells (HSPCs) toward myeloid- and erythroid-biased extramedullary hematopoiesis (EMH), expanding myeloid-derived suppressor cells (MDSCs) and erythroid progenitor cells (EPCs) that collectively foster immune evasion and metastatic cascades. Consequently, splenic resident immune cells, stromal cells and EMH-related pathways have surfaced as actionable therapeutic targets. In parallel, bidirectional crosstalk between the autonomic nervous system and splenic immunity fine-tunes homeostasis, systemic inflammation and antitumor responses-fueling rising interest in splenic neuromodulation as a therapeutic strategy. In addition, spleen-targeted nanoplatforms are emerging as promising tools to deliver immunomodulatory payloads with improved precision. Nonetheless, inherent structural and functional disparities between human and murine spleens complicate clinical translation of pre-clinical findings. This review provides a concise overview of human lymphoid organs and their functions, with a particular focus on splenic anatomy, cellular composition, and neural regulation. It further delineates tumor-induced splenic rewiring and discusses the prospects of exploiting the spleen as both a biomarker and a therapeutic target in oncology.

The PD-1/PD-L1 axis represents a well-established immunotherapeutic target. Nevertheless, anti-PD-1/PD-L1 therapeutics have shown limited efficacy in the management of solid tumors, particularly in the context of hepatocellular carcinoma (HCC). Among the various factors contributing to the resistance to anti-PD-1/PD-L1 therapy, tumor-associated macrophages (TAMs) have attracted significant interest because of the immunosuppressive properties. NPLOC4 has been explored as an antitumor drug target. However, whether NPLOC4 functions in TAMs or immunotherapy is unclear. Here, we report a new role for NPLOC4⁺ TAMs in inhibiting antitumor immune responses by facilitating the proteasomal degradation of RIG-I. Clinical specimens revealed that the number of NPLOC4⁺ TAMs are negatively correlated with the prognosis of patients with HCC. Proteomic data and in vitro/in vivo experiments demonstrated that NPLOC4 inhibits the type I interferon pathway in TAMs, promotes M2 polarization, and suppresses CD8⁺ T-cell infiltration, thereby creating an immunosuppressive microenvironment in HCC. NPLOC4 can bind to RIG-I and mediate its ubiquitination-mediated degradation, thus suppressing the type I interferon pathway. Animal studies have indicated that disulfiram/copper (DSF/Cu) can target the NPLOC4 protein, and that the combination of DSF/Cu with PD-1 therapy significantly inhibits HCC growth. In conclusion, targeting NPLOC4⁺ TAMs can significantly increase the resistance of HCC to anti-PD-1 therapy, which makes it a promising novel immune target for HCC treatment.

Triple-negative breast cancer (TNBC) and epithelial ovarian cancer (EOC) pose notable threats to the health of women. Given the poor prognosis associated with TNBC and EOC, new therapeutic agents must be explored urgently. Here, we identified triptonide (TN), a natural compound derived from the traditional Chinese herb Tripterygium wilfordii, as a potent antitumor agent. A series of functional assays showed that TN represses proliferation in TNBC and EOC cell lines, cell-derived xenograft, and patient-derived organoid models. Through molecular docking, molecular dynamics simulation, surface plasmon resonance, cell thermal shift assay, and drug affinity reaction target stability assays, we pinpointed PTGS2 as a direct target of TN. Mechanistically, TN binds to His-207 in PTGS2 and induces proteasome degradation of PTGS2 through recruiting E3 ubiquitin-protein ligase NEDD4. TN-induced PTGS2 downregulation leads to the inhibition of the JAK/STAT3/c-Myc signaling axis, resulting in suppression of tumor proliferation and the induction of autophagic cell death. In conclusion, our findings highlight TN as a promising candidate for TNBC and EOC treatment, acting through a novel mechanism involving targeted degradation of PTGS2 protein.

Intrinsic resistance to sunitinib in advanced renal cell carcinoma (RCC) remains a major barrier to improving patient survival outcomes. However, the molecular mechanisms driving this resistance remain incompletely elucidated. In this study, we first observed elevated glutamine levels in sunitinib-resistant RCC models; notably, glutamine deprivation substantially impaired the growth and proliferation of RCC cells. We further demonstrated that abnormal upregulation of GFPT2-a key enzyme in glutamine metabolism-was associated with reduced sunitinib sensitivity and enhanced drug resistance in RCC. Mechanistically, we uncovered that GFPT2 modulates cellular O-GlcNAcylation levels, which in turn enhances the stability and nuclear translocation of YAP1-ultimately contributing to reduced sunitinib sensitivity. In addition, we also identified an additional non-metabolic role of GFPT2: it directly interacts with the Kelch domain of KEAP1, thereby reducing NRF2 binding to this domain and suppressing NRF2 ubiquitination-dependent degradation. Consequently, this regulatory cascade dysregulates the transcription of downstream antioxidant genes (e.g., HMOX1 and NQO1), ultimately driving NRF2-dependent sunitinib resistance in RCC. Critically, this KEAP1-NRF2 axis-mediated mechanism operates independently of GFPT2's metabolic role in regulating O-GlcNAcylation. Collectively, our findings demonstrate that GFPT2 modulates sunitinib sensitivity and drives drug resistance in RCC via dual mechanisms: a metabolic pathway (O-GlcNAcylation-YAP1) and a non-metabolic pathway (KEAP1-NRF2). Targeting the non-metabolic functions of GFPT2 thus holds promise for enhancing sunitinib sensitivity in RCC while potentially mitigating treatment-related side effects.

Pancreatic cancer is a highly aggressive malignancy characterized by a progressively stiffened extracellular matrix, which promotes mechanical memory acquisition in cancer cells and facilitates malignant progression and metastasis. Despite its clinical significance, the mechanisms underlying matrix stiffening and mechanical memory formation remain poorly defined. This study demonstrates that a high-stiffness microenvironment induces mechanical memory in pancreatic tumor cells, which in further aggravates stromal remodeling and adversely affects prognosis. Under mechanically stiff conditions, pancreatic cancer cells exhibit pronounced enrichment of RNA modification-related and metabolic pathways, along with significantly increased m6A levels. Mechanistically, METTL14 enhances YAP1 expression through YTHDF3-mediated m6A-dependent translational regulation, while YAP1 in turn transcriptionally upregulates METTL14 via TEAD1, establishing a positive feedback loop that sustains mechanical memory. This METTL14-YAP1 axis activates CD166-EGFR-LOXL2 signaling, leading to enhanced collagen cross-linking and deposition, increased stromal stiffness, and maintenance of tumor stemness. These results identify the METTL14-YAP1 feedback loop as a core regulator of mechanical memory in pancreatic ductal adenocarcinoma, which drives stromal dysfunction and tumor progression through CD166-LOXL2 axis, and suggest targeting this loop as a potential therapeutic strategy to disrupt mechanical memory and ameliorate stiffness-induced remodeling.

Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignancy characterized by significant radioresistance and poor prognosis. We previously reported that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting cancer stem cell (CSC) properties and radioresistance in ESCC. This study focuses on the regulation of post-translational modifications (PTMs) of RSK4 and their effects on CSC properties and radioresistance. We demonstrate that RSK4 stability and activity are tightly regulated by phosphorylation and O-GlcNAcylation. GSK3β phosphorylates RSK4 at Thr402/Ser406, promoting its degradation via the FBXW7-dependent proteasomal pathway. Additionally, O-GlcNAcylation of RSK4 at Thr405 by OGT inhibits GSK3β-mediated phosphorylation, stabilizing RSK4 and enhancing CSC properties and radioresistance. This antagonistic relationship between phosphorylation and O-GlcNAcylation highlights a novel regulatory mechanism of RSK4 in ESCC. Moreover, targeting RSK4 O-GlcNAcylation with OSMI-4 destabilizes RSK4 and sensitizes ESCC to radiotherapy in both patient-derived xenograft and organoid models. Collectively, this study provides critical insights into the molecular mechanisms underlying ESCC radioresistance and identifies RSK4 O-GlcNAcylation as a potential therapeutic target to improve radiotherapy efficacy and overcome treatment resistance.

The gut-lung axis microbiota plays a pivotal role in shaping the tumor immune microenvironment (TIME) and regulating immunotherapeutic responses in lung cancer. This review highlights that pulmonary and gut microbial dysbiosis drives lung cancer development through inducing chronic inflammation, remodeling the immune microenvironment, and reprogramming metabolism. Lung cancer patients exhibit distinct microbial signatures characterized by altered microbiotal diversity and enrichment of specific taxa like Streptococcus, Veillonella, and Bacteroidetes in the airways, along with gut microbial shifts involving decreased Firmicutes/Bacteroidetes ratio. These microbial alterations promote tumor progression via activation of pro-inflammatory pathways (e.g., interleukin-17 (IL-17)/interleukin-23 (IL-23) axis) and suppression of antitumor immunity.Notably, the gut-lung microbiome exerts a profound impact on immunotherapeutic efficacy: responders are enriched with beneficial microbes like Akkermansia muciniphila and Bifidobacterium that enhance CD8⁺ T cell responses, while non-responders show elevated levels of Gammaproteobacteria and Fusobacterium associated with immunosuppression. Regulatory mechanisms include systemic immune modulation by microbial metabolites such as short-chain fatty acids, as well as activation of key signaling pathways including cGAS-STING and CD40L-CD40/NF-κB. Emerging translational applications encompass lung cancer diagnosis and immunotherapeutic response prediction via microbial biomarkers, as well as therapeutic interventions including fecal microbiota transplantation (FMT) and probiotic supplementation. Future studies should clarify microbe-host interaction mechanisms and develop personalized microbiota-based strategies to overcome immunotherapy resistance, offering the potential to revolutionize precision oncology through integrating microbiota modulation with conventional therapies.

The ERK5 signaling pathway has recently emerged as a critical regulator of soft tissue sarcoma (STS) biology, contributing to tumor initiation, progression, and maintenance. In this study, we identify VCAN, a chondroitin sulfate proteoglycan, as a novel transcriptional target of ERK5 and a central mediator of ERK5-related oncogenesis. Through a combination of genetic (silencing, overexpression) and pharmacological approaches, applied in both a chemically induced murine sarcoma model and several human STS cell lines, we demonstrate that ERK5 positively regulates VCAN expression. Functionally, VCAN silencing (by shRNAs) recapitulates the phenotypes of ERK5 silencing, including impaired migration, adhesion, proliferation, and tumorigenesis. Conversely, VCAN overexpression rescues these effects, confirming its essential role in ERK5-mediated oncogenesis. Furthermore, transcriptomic profiling reveals that VCAN accounts for a substantial portion of ERK5-regulated gene expression program. Analyses of human STS patient samples reveal significantly elevated mRNA levels of both VCAN and ERK5 compared to normal tissues. Notably, a strong correlation between VCAN and ERK5 expression, both at mRNA and protein levels, emerged in biopsies from leiomyosarcomas and undifferentiated pleomorphic sarcomas. Together, these findings uncover VCAN as a key effector in ERK5-driven tumorigenesis and highlight the ERK5/VCAN signaling axis as a promising therapeutic target in soft tissue sarcomas.

Sirtuin 1 (SIRT1) and Sirtuin 2 (SIRT2) are NAD⁺-dependent deacetylases that regulate cancer metabolic stress, exerting their effects primarily through post-translational modification of metabolic enzymes and transcription factors. They modulate glucose, lipid, and mitochondrial metabolism, as well as immune metabolism responses within the tumor microenvironment. Depending on cellular context, they can promote or suppress tumor growth by directing energy production, redox balance, and metabolic adaptation. These context-dependent and often opposing activities constitute a Yin-Yang mode of regulation in cancer metabolism, reflecting a dynamic balance between metabolic activation and constraint. Autophagy has emerged as a critical metabolic integration node regulated by both SIRT1 and SIRT2, linking nutrient sensing, mitochondrial quality control, and stress adaptation. This review summarizes recent advances in understanding how SIRT1 and SIRT2 coordinate tumor metabolism and discusses therapeutic strategies that target their regulatory balance to reprogram cancer metabolism. SIRT2 also functions as a metabolic checkpoint that restrains CD8⁺ T cell effector metabolism, providing a rationale for combining SIRT2 inhibition with immune checkpoint blockade in metabolically stressed tumor microenvironments.