Cancer is not biologically confined to the tumor bed. Cachexia, fatigue, metabolic dysfunction, circadian disruption, and immune dysfunction reflect disturbances that local models alone cannot fully explain. The brain is well positioned to participate in these processes because it continuously samples circulating signals and coordinates endocrine and autonomic responses. Yet the afferent side of this communication has received less attention than its downstream consequences. Here, we synthesize evidence showing that cytokines, hormones, metabolites, and cargo carried by extracellular vesicles can engage central sensory interfaces and integrative regions, particularly circumventricular organs and hypothalamic and brainstem circuits. We use the term Endocriception to describe afferent humoral sensing and early central decoding of circulating biochemical signals, and focus here on how tumor- and host-associated changes engage this process in cancer. Central neuroendocrine governance refers to the subsequent integration of this information and the generation of autonomic and endocrine outputs. Persistent inflammation, stress, circadian disruption, and impaired feedback may gradually reconfigure this regulatory system. The resulting changes can affect systemic immunity, metabolism, behavior, and host tolerance of cancer. Evidence is strongest for a limited number of pathways, whereas many proposed links remain incomplete or dependent on tumor type and experimental context. We therefore present central neuroendocrine governance as a working framework for organizing current evidence and guiding mechanistic studies, biomarker development, and interventions aimed at restoring host physiology.

Sensitive biomarkers for recurrence risk stratification, recurrence surveillance and adjuvant therapy guidance are of unmet need for patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). Herein, we explored the potential of profiling circulating tumor DNA (ctDNA) for prediction and prevention of recurrence in HCC after LT. HCC patients (n=91) who underwent LT were prospectively enrolled. ctDNA was assayed using next-generation sequencing from perioperative plasma (n=408). Associations between ctDNA status with clinicopathological parameters, tumor recurrence, and adjuvant treatment effect were analyzed. Higher preoperative ctDNA burden correlated with microvascular invasion (median: 45.0 vs 5.1 MTM/mL, P=0.003) and recurrence (156.2 vs 7.7 MTM/mL, P<0.001). ctDNA clearance was noted in 87.7% patients after LT and patients who kept positive postoperative ctDNA showed higher recurrence risk (HR=8.86, P<0.001), especially early recurrence (within 1 year; 75.0% vs 10.1%, P<0.001). During follow-up, positive longitudinal ctDNA was similarly predictive of recurrence (HR=36.50, P<0.001). The AUC of longitudinal ctDNA for predicting recurrence was 0.930-significantly higher than alpha-fetoprotein (0.655, P<0.001). Longitudinal ctDNA detected radiologically evidenced recurrence with a median lead time of 5.1 months compared to standard-of-care surveillance. Among patients who received adjuvant therapy, those with positive postoperative ctDNA could benefit (HR=0.11, P=0.003) and those with decreased ctDNA burden following treatment experienced longer interval from ctDNA positivity to recurrence (HR=0.17, P=0.006). Serial ctDNA analysis demonstrates strong prognostic value, capable of heralding tumor recurrence prior to radiological recurrence and measuring treatment efficacy. Its integration into clinical practice of HCC provides unique opportunities for adjuvant therapy decision-making following LT.

The specific mechanisms of Verbascoside (VB) in ovarian cancer (OC) remain insufficient. This study aimed to explore the anti-tumor mechanisms of VB in OC, focusing on its ability to modulate the immunosuppressive tumor microenvironment (TME), particularly through targeting neutrophil infiltration and neutrophil extracellular traps (NETs). The anti-tumor and anti-NETosis efficacy of VB was evaluated in vivo using subcutaneous, orthotopic, and pulmonary metastasis mouse models of OC. Microproteomics and bioinformatics analysis identified the direct molecular target of VB and the key neutrophil chemoattractant. The underlying mechanisms were validated in vitro and in vivo (using SKOV3, ID8, and neutrophils), alongside loss-of-function approaches. The combination of VB with anti-PD-1 immunotherapy was also assessed. VB inhibited OC proliferation/metastasis, promoted anti-tumor immunity, and suppressed neutrophil infiltration and NETosis. Neutrophil depletion attenuated VB's anti-metastatic effect. Microproteomics and bioinformatics screening identified IRAK4 as a direct molecular target of VB and CXCL5 as a key neutrophil chemoattractant. SPR confirmed the direct binding between VB and IRAK4, and molecular docking revealed specific hydrogen bond interactions. Mechanistically, VB treatment or IRAK4 knockdown suppressed CXCL5 expression, and consequently reduced neutrophil infiltration and NETosis. Consistently, CXCL5 overexpression abrogated the inhibitory effects of VB on neutrophil NETosis and recruitment. Furthermore, VB synergized with anti-PD-1 therapy, thereby achieving superior tumor growth inhibition, reduced Ki67 expression, and enhanced CD8+ T cell infiltration. In conclusion, VB exerts potent anti-tumor effects in OC by targeting the IRAK4/CXCL5 axis, thereby inhibiting neutrophil infiltration and NETosis, reshaping the immunosuppressive TME, and restoring anti-tumor immunity.

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that supports the growth of approximately 5-10% of human tumors and represents an attractive but insufficiently explored therapeutic target. CRISPR-based functional genomics has emerged as a powerful approach to systematically interrogate ALT biology and identify genetic dependencies associated with the ALT state. In this Review, we discuss the CRISPR-based strategies applied to ALT, including hypothesis-driven targeted loss-of-function screens, phenotype-driven optical screens, in silico mining of large-scale dependency datasets, and genome-wide screens in ALT-adjacent states. Across these approaches, recurrent dependencies converge on pathways mediating replication stress buffering, DNA repair, and telomere maintenance, including FANCM, SMARCAL1, and SUB1. Collectively, these findings support a model in which ALT-positive cells rely not on a unique ALT-specific factor, but rather on stress-buffering mechanisms that prevent chronic telomeric dysfunction from triggering replication catastrophe and cell death, highlighting these pathways as promising candidates for further therapeutic investigation.

Prolonged colonic inflammation and ulcerative colitis lead to colon cancer. The rapid growth and treatment-resistant nature of these tumors are primarily influenced by an immunosuppressive tumor microenvironment, which is led by tumor-associated macrophages (TAMs). However, factors influencing or regulating the immunosuppressive nature of TAMs have not been sufficiently studied. In this manuscript, we use a mouse model of colitis-associated colorectal cancer (CRC) to demonstrate that WNT expression in TAMs regulates their immunosuppressive function by inhibiting Glycogen synthase kinase-3 beta (GSK-3β) within the macrophages, possibly through an autofeedback loop. GSK3β is a positive regulator of PD-1 and PD-L1 expression in macrophages and promotes an immunosuppressive microenvironment. Therefore, GSK-3β inhibition alters the immunosuppressive nature of the immune microenvironment and effectively controls tumor growth. In Csf1r.iCre; Porcn[fl/fl] mice, the absence of macrophage-derived WNT promotes tumor growth in the model of colitis-associated colon cancer. Absence of macrophage-derived WNT stabilizes GSK-3β in macrophages and promotes an immunosuppressive tumor microenvironment. We also show that pharmacological inhibition of GSK-3β in a macrophage-specific manner, achieved by systemic delivery of a lipo-GSK3β inhibitor, effectively inhibits tumor growth. Therefore, this manuscript demonstrates for the first time that the macrophage-specific modulation of GSK3β can be a potential target to treat colitis-associated colon cancer.

Metal ions serve as key regulators of the dynamic equilibrium within the tumor microenvironment (TME). In recent years, the TME has emerged as a central regulatory hub for tumor initiation, progression, and metastasis; its complexity has become both a frontier and a major challenge in oncology research. Current therapies are often constrained by immune tolerance, metabolic heterogeneity, and microenvironment-mediated escape mechanisms, necessitating breakthroughs in novel targets and strategies. Metal ions, functioning as enzyme cofactors, signaling molecules, and redox regulators, profoundly affect tumor progression by modulating redox homeostasis, immune responses, and metabolic reprogramming. This review provides a comprehensive overview of recent advances in metal ion-mediated regulation of the TME. It focuses on elucidating the multidimensional mechanisms by which metal ions facilitate immunogenic remodeling and metabolic interactions, and prospectively explores innovative metal-ion-based diagnostic and therapeutic strategies. It further highlights the potential of personalized metal metabolomics to advance precision oncology and facilitate the clinical translation of metal ion-based theranostic strategies.

Reciprocal interactions between immune and stromal cells are increasingly recognized as major determinants of colorectal cancer (CRC) progression. However, the specific macrophage and fibroblast states cooperating to establish and sustain a tumor-promoting microenvironment remains incompletely understood. Here, we identify a self-reinforcing inflammatory circuit linking monocyte-derived IL-1β[+] macrophages with IL1R1[+] cancer-associated fibroblasts (CAFs) in CRC. Integrated single-cell transcriptomic analyses of human CRC revealed a marked expansion of IL1B-associated inflammatory macrophages and IL1R1[+] inflammatory CAFs, with their respective and combined transcriptional signatures associated with adverse clinical outcomes. Pseudotime analysis and Ms4a3 lineage tracing supported a predominantly monocyte-derived origin of IL-1β[+] macrophages in the tumor microenvironment. Mechanistically, macrophage-derived IL-1β activated IL1R1 signaling in fibroblasts, promoting the acquisition and expansion of an inflammatory CAF state. Myeloid Il1b deletion or fibroblast-lineage Il1r1 deletion disrupted this interaction and suppressed tumor growth in vivo. In turn, IL1R1[+] CAFs produced abundant CCL2, which recruited CCR2[+] monocytes and replenished the IL-1β[+] macrophage population. Fibroblast-lineage Ccl2 deletion, myeloid Ccr2 deletion, and CCL2 rescue experiments established the functional requirement of the CCL2-CCR2 axis for closure of this reciprocal circuit. Acquisition of the IL-1β[+] inflammatory macrophage program was further supported by coordinated NF-κB and AP-1 activity, with RELA and JUN/FOS contributing to IL1B transcriptional regulation. Finally, therapeutic blockade of either IL-1β or CCL2 disrupted the macrophage-CAF circuit, increased intratumoral CD8[+] T-cell responses, and enhanced the antitumor efficacy of anti-PD-1 therapy. Collectively, our findings establish the IL-1β-IL1R1-CCL2-CCR2 axis as a self-amplifying immune-stromal circuit that sustains a tumor-promoting and immunosuppressive microenvironment in CRC. By demonstrating that disruption of this circuit restores antitumor immune activity and sensitizes tumors to PD-1 blockade, our study provides a mechanistic and preclinical rationale for targeting IL-1β-CCL2-mediated macrophage-CAF crosstalk as a combination strategy to improve immunotherapy responses in CRC.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is characterized by a highly infiltrated yet immunosuppressive tumor microenvironment (TME), in which tumor-associated macrophages (TAMs) contribute to disease progression. Here, we identify an extracellular vesicle (EV)-mediated LMP1-NF-κB-LIF signaling axis that promotes macrophage reprogramming and immune suppression in NPC. Single-cell transcriptomic analysis revealed that EV exposure induces transcriptional remodeling across tumor and immune-cell populations, accompanied by an increased proportion of TAMs within the myeloid compartment. NPC-derived EVs were taken up by macrophages, where EV-associated LMP1 induced NF-κB activation, LIF expression, and polarization toward an immunosuppressive phenotype. Loss- and gain-of-function studies, together with structure-function analyses of the LMP1 CTAR1/CTAR2 domains, further supported the requirement of these CTAR domains for efficient NF-κB activation and LIF induction. Functionally, EV-educated macrophages exhibited impaired phagocytic activity and promoted inhibitory T-cell responses. In zebrafish, 3D spheroid, and mouse xenograft models, EV-educated macrophages promoted NPC growth and vascular dissemination, whereas blockade of LIF signaling with soluble LIFR attenuated these effects. Tumor LIF expression positively correlated with CTLA4 expression. In NPC tissues, LIF expression was preferentially associated with stromal macrophages, and elevated stromal LIF expression was associated with metastasis, advanced nodal disease, and advanced clinical stage. Stromal immune-cell LMP1 expression also correlated with LIF expression and was higher in patients who developed metastasis. Collectively, these findings support an EV-associated LMP1-NF-κB-LIF axis that links EBV-positive NPC cells to macrophage-mediated immune suppression and tumor progression and provide a basis for further investigating this pathway as a potential therapeutic target.

Immunotherapy has improved outcomes for patients with breast cancer, yet therapeutic resistance remains a major clinical challenge. Therefore, we integrated single-cell and spatial transcriptomic data from breast cancer cohorts treated with immune checkpoint inhibitors to identify resistance-associated cellular populations and pathways, with validation across eight independent bulk RNA-seq immunotherapy cohorts. Cancer-associated fibroblasts (CAFs) were isolated from anti-PD-1-resistant breast tumors for functional studies, including in vitro co-culture and in vivo models. Mitochondrial function and metabolic alterations were assessed by flow cytometry, transmission electron microscopy, ATP and adenosine quantification, and JC-1 staining. Tumor mitochondrial metabolism was markedly upregulated in anti-PD-1 non-responders and consistently associated with poor therapeutic response across validation cohorts. MDK-expressing CAFs were enriched in resistant tumors, exhibited strong interactions with tumor cells, and were negatively associated with intratumoral CD8+ T cell infiltration. Single-cell source contribution and depletion analyses identified CAF-derived MDK as the major paracrine mediator linking stromal signaling to tumor metabolic adaptation and immune suppression. Mechanistically, MDK activated SDC1-dependent PI3K/AKT/mTOR signaling in cancer cells, promoting mitochondrial metabolic reprogramming, ATP production, and CD38/CD73-dependent extracellular adenosine accumulation, thereby suppressing CD8+ T cell cytotoxicity. Receptor-depletion experiments further identified SDC1 as the principal functional receptor mediating these effects. Importantly, CAF-specific MDK depletion or pharmacological MDK inhibition enhanced anti-PD-1 efficacy and restored CD8+ T cell effector activity in vivo. Collectively, MDK+ CAFs facilitate anti-PD-1 resistance via mitochondrial rewiring and adenosine-mediated immunosuppression, supporting the MDK-SDC1 axis as a potential therapeutic target for overcoming resistance and improving immunotherapy efficacy in breast cancer.

Atovaquone is an approved antimalarial drug which could sensitise tumours to radiation and may modulate tumour immune microenvironment. Here we evaluated the triple combination of radiation with atovaquone plus anti-PD-L1 in HNSCC syngeneic mouse tumour models. We observed significant tumour growth delay induced by the triple combination treatment with differential responses in three different mouse models. There was complete tumour eradication in 6 of 12 mice in the MOCL1 model but not in the other two murine models. The triple combination was associated with increased populations of CD8[+]-T Granzyme B+ cells as well as decreased populations of Tregs, CD11b[+]Gr1[+] granulocytic MDSCs and CD11b[+] Ly.6G[+] neutrophils. Atovaquone inhibited EGFR and its downstream signalling as well as reduced PD-L1 expression. The differential antitumour effects of the triple combination may be due to different basal and post-treatment levels of PD-L1, pERK1/2 and pS6, in particular, their levels were reduced by atovaquone +/- RT in MOCL1 models and not in the other two murine models. Radiotherapy plus atovaquone combination increased cell cycle arrest in G2/M phase, which led to inhibition of DNA damage repair by homologous recombination and increased cell death. We also observed increased activation of CD8[+]-T cells that led to enhanced killing in our HNSCC patient-derived organoid models treated with the triple combination of radiotherapy and atovaquone plus PD-1/PD-L1 blockade. Overall, our results suggest that the triple combination of radiotherapy and atovaquone plus PD-1/PD-L1 blockade has the potential to increase the efficacy of radiotherapy and/or immunotherapy. Thus, this may provide a rationale to further validate this triple combination of radiotherapy and atovaquone plus PD-1/PD-L1 blockade in clinical trials to improve treatment outcomes.

Rising incidence of colorectal cancer (CRC) and limited therapeutic options highlight the urgent need to define the drivers of its progression. The SPP1[+] tumor-associated macrophage (TAM) subset identified by single-cell transcriptomics is a functionally dominant population that extends beyond the classical M1/M2 paradigm. Here, we dissected the molecular mechanisms by which SPP1[+] TAMs reprogram tumor progression and determined whether the gut microbiota regulates this process in colorectal cancer. Using a multi-platform strategy integrating clinical specimens, murine models and CRC cell lines, we found that SPP1[+] TAMs increase progressively during CRC evolution and exhibit crosstalk with malignant epithelial cells, and their abundance is associated with adverse clinical outcome. Integrative analysis reveals a significant positive correlation between SPP1 and ARG2 expression. Further, TAM-derived SPP1 engages CD44 on CRC cells to induce ARG2 expression. Mechanistically, ARG2 facilitates the interaction between USP10 and c-Myc to deubiquitinate and stabilize c-Myc, which transactivates the glycolytic enzyme HK2, driving Warburg metabolism that fuels CRC cell proliferation. Moreover, ARG2 secreted by CRC cells is internalized by TAMs, which reciprocally upregulates SPP1, creating a feed-forward loop that drives a pro-tumorigenic microenvironment. Notably, Bifidobacterium longum downregulates CD44 expression on tumor cells, thereby disrupting the SPP1-ARG2 axis and attenuating CRC progression. These findings identify the SPP1-ARG2 circuit as a therapeutic target and propose B. longum as a microbiome-derived precision adjuvant therapy for CRC suppression.

Tumor drug resistance is still the core obstacle limiting the long-term benefit of modern anticancer therapy, especially in the context of treatment tolerance, persistence of minimal residual disease (MRD) and recurrence after treatment. Increasing evidence has shown that therapy-associated myeloid niches can involve cell recruitment, enrichment of pre-existing populations, or state reprogramming, together with local relationships among myeloid cells, tumor cells, stroma, vessels, and other immune cells. These niches can support residual tumor-cell survival, immune escape, local regrowth, and distant dissemination through overlapping mechanisms linking fibrotic exclusion and perivascular organization with hypoxic metabolic suppression and myeloid replenishment. The formation of neutrophil extracellular traps, failure of antigen uptake and presentation, impaired T-cell priming, and phagocytic escape can further sustain treatment tolerance. Focusing on the myeloid cell state and common molecular circuits, this article presents an evidence assessment framework that interprets spatial and clinical associations alongside functional and pharmacologic findings without assigning hierarchical ranks. It summarizes lessons from clinical failure, considering potentially limited target contributions, compensatory pathways, inadequate exposure, and toxicity, while distinguishing drug exposure and local pharmacodynamic changes from clinical benefit. Candidate biomarkers, intervention windows, and selective delivery approaches require validation to guide mechanism-matched combinations. In the future, longitudinal tissue analyses, functional validation, and prospective studies should test whether these combinations provide durable benefit with acceptable safety in defined patient populations and treatment settings.

Although neoadjuvant immunochemotherapy (NICT) has improved survival in locally advanced gastric cancer (GC) and gastroesophageal junction cancer (GEJC), lymph node metastasis (LNM) patterns following NICT remain undefined. We aimed to characterize topographical LNM patterns after NICT and evaluate the association between lymphadenectomy extent, surgical approach, and survival outcomes. Data were pooled from 4 prospective clinical trials (NEOSUMMIT-01 - 04), comprising 126 patients with GC (n = 61) or GEJC (n = 65) undergoing curative gastrectomy following NICT. ypN0 was achieved in 71 patients (56%). In GEJC, station No. 3, 7 were high risk; No. 1, 2, 9, and 11 were intermediate risk; and No. 4, 5, 6, 8, 12 were low risk. In GC, station No. 12 was low-risk; D1 stations (No. 1, 3, 4, 5, 6, 7) were high-risk, D1+ stations (No. 8, 9) and No. 11 were intermediate-risk. At a median follow-up of 36.2 months, 24-month EFS and OS rates were 76.4% and 90.5%. Nodal yield (≥ 30 vs. < 30) was not significantly associated with EFS (P = .611) or OS (P = .911). In exploratory comparisons within the GEJC cohort, EFS (P = .219) and OS (P = .290) did not differ significantly between proximal and total gastrectomy. In GEJC, distal perigastric lymph node stations (No. 4, 5, 6, and 12) exhibited low metastasis rates, while exploratory survival outcomes support prospective clinical trials of proximal gastrectomy in appropriately selected patients. Conversely, the broader residual nodal involvement in GC reinforces the continued role of standard D2 lymphadenectomy.

Antiapoptotic buffering in solid tumors is generally mediated by both BCLXL and MCL1, so that BH3 mimetic drugs targeting only one have limited efficacy. To identify agents that may sensitize tumors to BH3 mimetics targeting BCLXL, we screened prostate cancer cells against a panel of mitochondria-targeted drugs in combination with navitoclax, a BH3 mimetic targeting BCL2 and BCLXL. Homoharringtonine (HHT) in combination with navitoclax and as a single agent emerged as a potent inducer of apoptosis. HHT has been identified as an inhibitor of protein translation, and proteomic analysis showed broad suppression of translation-related pathways, while immunoblotting demonstrated rapid decreases in short-lived proteins, including MCL1. HHT dose response and time course studies showed marked declines in MCL1 within 2 hours that were associated with apoptosis in response to BCLXL inhibition with navitoclax or A1331852. Further cell viability assays showed synergy between HHT and BCLXL inhibitors in multiple prostate, lung, and colorectal cancer cell lines. HHT monotherapy in vivo caused tumor regression in two prostate cancer xenograft models. Analysis of tumor tissue taken at 4 hours after dosing showed decreases in MCL1 and MYC, indicating that HHT levels obtainable in vivo are adequate to deplete short-lived proteins and potentially sensitize to BH3 mimetics targeting BCLXL. These findings support further exploration of HHT as a single agent in solid tumors and establish a rationale for investigating safer, tumor-selective approaches to combine HHT-mediated translational inhibition with BCLXL targeting.

Hepatocellular carcinoma (HCC) is driven by cancer stemness and an immunosuppressive tumor microenvironment, which collectively contribute to therapeutic resistance. While the RNA-binding protein HNRNPC has been implicated in tumor progression, it has primarily been characterized as a downstream effector, and its autonomous regulatory functions, particularly in governing cancer stemness, remain entirely unexplored. Through multi-omics analyses of HCC cohorts, we identified HNRNPC as a pivotal driver of a high-risk molecular subtype. Mechanistically, HNRNPC expression was transcriptionally activated via WDR5/KMT2A complex-mediated deposition of H3K4me3 at its promoter. Functionally, HNRNPC was essential for maintaining cancer stemness, promoting tumor growth and metastasis, and conferring oxaliplatin resistance. Notably, depletion of HNRNPC reprogrammed the immunosuppressive microenvironment by enhancing CD8[+] T cell infiltration, reducing T cell exhaustion, and polarizing macrophages toward an M1-like anti-tumor phenotype. At the molecular level, HNRNPC bound to the m6A-modified 3'UTR of CD24 mRNA in an RNP2 motif-dependent manner, thereby enhancing its stability and elevating CD24 protein expression. Therapeutically, we developed a novel lipid nanoparticle (LNP) encapsulating siRNA against HNRNPC. Systemically administered AP-EG-si potently suppressed tumor growth, attenuated stemness, and synergized with anti-PD-L1 therapy to enhance anti-tumor immunity. Our findings thus unveil the H3K4me3-HNRNPC-CD24 axis as a central epigenetic and post-transcriptional regulatory pathway that coordinately drives HCC stemness and immune evasion, nominating HNRNPC-targeted nanotherapy as a promising strategy for advanced HCC.