Weng YS, Chiang IT, Dong DC
… +4 more, Liu YC, Lan KL, Tsai CL, Hsu FT
Cancer Lett
· 2026 Jul · PMID 42401334
·
Publisher ↗
Given the high heterogeneity and immunosuppressive nature of glioblastoma (GBM), standard monotherapies such as chemotherapy, radiotherapy, and immunotherapy show limited efficacy. Therefore, urgent combined treatment st...Given the high heterogeneity and immunosuppressive nature of glioblastoma (GBM), standard monotherapies such as chemotherapy, radiotherapy, and immunotherapy show limited efficacy. Therefore, urgent combined treatment strategies-like immunostimulatory recombinant proteins-are needed. Compared to interleukin-2 (IL-2), IL-15 is a promising agent without the drawback of activation-induced cell death (AICD). We engineered a recombinant human IL-15 fused with an albumin-binding domain (hIL-15-ABD) to prolong IL-15's half-life and enhance blood-brain barrier penetration. We evaluated whether hIL-15-ABD could boost the efficacy of immune checkpoint inhibitors (ICIs) in a GBM model. Our findings indicate that hIL-15-ABD significantly improves the anti-GBM effects of anti-PD-L1 and anti-PD-1 therapies by increasing M1 macrophage populations, activating cytotoxic T cells, and promoting natural killer cell responses in an orthotopic GBM model. hIL-15-ABD enhanced the efficacy of both anti-PD-L1 (10F.9G2) in C57BL/6 mice and anti-PD-1 (nivolumab) in a GL261 model using humanized PD1/ mice. Notably, hIL-15-ABD not only boosts immunostimulation but also reduces the proportions of immunosuppressive cells, including regulatory T cells and MDSCs, in the tumor microenvironment. Additionally, hIL-15-ABD appears to target FGF-2 and its receptors, inactivating the FGF-2/FGFR1/2 pathways. In summary, hIL-15-ABD shows potential as an immunostimulatory agent for ICIs in GBM treatment.
Cancer Lett
· 2026 Jul · PMID 42398852
·
Publisher ↗
Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment (TME), shaping immune surveillance, stromal architecture, metastatic progression, and therapeutic resistance across solid tumors. Alth...Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment (TME), shaping immune surveillance, stromal architecture, metastatic progression, and therapeutic resistance across solid tumors. Although traditionally classified into heterogeneous subtypes, emerging evidence indicates that CAF phenotypes are not fixed lineages, but dynamic stress-adaptive states continuously reshaped by hypoxia, oxidative stress, nutrient deprivation, metabolic pressure, and therapy-induced injury. These pressures reprogram CAFs transcriptional, metabolic, and secretory programs, enabling CAFs to amplify tumor-promoting signals that reinforce immunosuppression, extracellular matrix (ECM) remodeling, metastatic niche formation, and treatment resistance. Viewing CAF biology through this stress-adaptation framework provides a mechanistic explanation for the limited success of indiscriminate stromal depletion strategies and highlights the need for more selective, context-aware therapeutic intervention. In this review, we examine how microenvironmental and therapeutic stress rewires CAF identity and function across tumor progression, integrating insights from single-cell, spatial, and translational evidence. We further discuss emerging strategies aimed at disrupting stress-adaptive CAF programs, including modulation of inflammatory signaling, stromal mechanotransduction, metabolic dependencies, and senescence-associated secretory phenotypes. Reframing CAFs as dynamic stress-responsive hubs rather than static stromal subtypes may provide a conceptual foundation for next-generation stromal-targeted therapies designed to overcome immunosuppression and therapeutic resistance.
Wang J, Ma H, Feng B
… +7 more, Fu Y, Lu C, Fei M, Zhang Y, Dong B, Li Y, Liu J
Cancer Lett
· 2026 Jul · PMID 42398851
·
Publisher ↗
Aldo-keto reductase family 1 member C3 (AKR1C3) is a pivotal metabolic enzyme involved in arachidonic acid (AA) metabolism and cancer metabolic reprogramming, which plays a critical role in the initiation and progression...Aldo-keto reductase family 1 member C3 (AKR1C3) is a pivotal metabolic enzyme involved in arachidonic acid (AA) metabolism and cancer metabolic reprogramming, which plays a critical role in the initiation and progression of glioblastoma (GBM). We integrated single-cell and transcriptome data to characterize AA metabolism features in GBM and identify the key gene AKR1C3. Using CCK8 assays, wound-healing assays, transwell assays, and mouse tumor formation experiments, we elucidated the effects of AKR1C3. Dual-luciferase reporter assays and ChIP-PCR experiments were performed to investigate the regulation of transcription factor JUN on AKR1C3 expression. RNA-seq analysis, combined with rescue experiments, demonstrated that AKR1C3 significantly regulates the RhoA/ROCK pathway. Arachidonic acid metabolism is closely associated with clinical outcomes in glioma, with AKR1C3 identified as a key gene within this pathway. AKR1C3 knockdown enhanced tumor cell proliferation, migration, and invasion, whereas AKR1C3 overexpression suppressed these malignant behaviors. In vivo experiments further confirmed the inhibitory effect of AKR1C3 on glioma progression. Dual-luciferase reporter and ChIP-PCR assays demonstrated that JUN acts as an upstream regulator of AKR1C3. ELISA results indicated that AKR1C3 overexpression reduced cellular PGD2 levels. RNA-seq analysis suggested that the RhoA/ROCK pathway was a downstream effector of AKR1C3, and exogenous PGD2 supplementation could reverse AKR1C3-mediated regulation of this pathway. We identified curcumin, a natural product with anti-cancer metabolic regulatory activity, as an upstream modulator that suppresses JUN expression, thereby activating the JUN/AKR1C3 axis and inhibiting malignant phenotypes in GBM cells. JUN/AKR1C3 axis influences glioma progression via modulating PGD2-mediated RhoA/ROCK Signaling.
Wu S, Li S, Zheng Y
… +20 more, Zhang L, Pan J, Zhao Y, Lin Y, Lin J, Pan Q, Lin J, Chen S, Huang Z, Lin D, He M, Chen Y, He H, Wang P, Chen S, Lian R, Li C, Zhang J, Xu H, Xu Y
Cancer Lett
· 2026 Jul · PMID 42398850
·
Publisher ↗
SMARCA4-deficient non-small cell lung cancer (SD-NSCLC) is associated with poor prognosis and lacks a standard treatment strategy. This multicenter retrospective study evaluated immunotherapy-based regimens and character...SMARCA4-deficient non-small cell lung cancer (SD-NSCLC) is associated with poor prognosis and lacks a standard treatment strategy. This multicenter retrospective study evaluated immunotherapy-based regimens and characterized the immune features of advanced SD-NSCLC using next-generation sequencing, flow cytometry, multiplex immunofluorescence, single-cell RNA and TCR sequencing, and a CRISPR/Cas9-mediated SMARCA4 knockout model. A total of 162 patients with advanced SD-NSCLC were enrolled from four Chinese cancer centers. Genomic analysis identified TP53, KEAP1, STK11, and KRAS as the primary co-mutated genes. Compared to single-agent chemotherapy, immunotherapy combined with chemotherapy and antiangiogenesis therapy demonstrated significantly longer median progression-free survival (mPFS) (12.10 vs. 2.77 months, p < 0.001). Furthermore, responders to this combination also exhibited elevated CD8 T cell infiltration (p < 0.01). In vivo, the three-drug combination regimen significantly inhibited the growth of SMARCA4-knock-out mouse tumor cells in mice, increased infiltration of CD8 T cells, and reduced the presence of regulatory T cells (Tregs) in the tumor microenvironment. In this mouse model, single-cell RNA-seq revealed a significant decrease in CTLA4 Tregs with active intercellular communication following anti-PD-1 therapy. Ex vivo experiments demonstrated that treatment with anti-PD-1 markedly reduced the proportion of Tregs and concurrently increased the proportions of IFN-γ and TNF-α producing cells. Lastly, single-cell TCR-seq confirmed the expansion of specific TCR clones, particularly within CCR7 and LEF1 naive T cells. Collectively, these findings suggest that immunotherapy-based combination regimens may provide substantial clinical benefit for patients with SD-NSCLC by enhancing CD8 T cell activity, suppressing CTLA4 Tregs, and expanding tumor-reactive TCR clones.
Wang YZ, Wang YG, Pan Y
… +6 more, Gang XY, Yan JS, Wang XP, Tang HL, Li HM, Zhao MF
Cancer Lett
· 2026 Jul · PMID 42392400
·
Publisher ↗
Early-onset lung cancer, commonly defined as disease diagnosed at or before 50 years of age, represents a growing but insufficiently characterized subset of lung cancer in clinical practice. However, much of the evidence...Early-onset lung cancer, commonly defined as disease diagnosed at or before 50 years of age, represents a growing but insufficiently characterized subset of lung cancer in clinical practice. However, much of the evidence informing current diagnostic and therapeutic practice has been generated from age-unselected or older, smoking-dominant populations and may not fully capture the clinical characteristics of younger patients. Consequently, younger individuals with lung cancer may face delayed risk recognition, incomplete molecular evaluation, and treatment decisions not fully informed by age-associated clinicobiological features. Accumulating evidence indicates that early-onset non-small cell lung cancer (NSCLC) is enriched for actionable oncogenic alterations, particularly gene fusions and selected HER2/ERBB2 alterations, and is frequently associated with lower tumor mutational burden and a less inflamed tumor microenvironment. Although these features do not yet establish early-onset NSCLC as a separate treatment category, they support age-informed refinement of guideline-based management, particularly in initial molecular testing, interpretation of immunotherapy-relevant immune features, treatment transitions, and survivorship planning. In this review, we synthesize current evidence on disease burden, etiologic heterogeneity, age-related genomic features, and treatment-relevant tumor immune context in early-onset lung cancer, with a focus on issues relevant to clinical interpretation and management prioritization. We further outline age-informed clinical management for molecular evaluation, resistance reassessment, and survivorship care, aiming to complement rather than replace established NSCLC guidelines for patients aged ≤50 years.
Carrabotta M, Manara MC, Landuzzi L
… +10 more, Simonetti E, Nesca A, Pellegrini E, Maioli M, Avnet S, Ruzzi F, Salamanna F, Gambarotti M, Lollini PL, Scotlandi K
Cancer Lett
· 2026 Jul · PMID 42392399
·
Publisher ↗
Ewing sarcoma (EwS) shows a limited clinical response to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), despite promising preclinical data. In this study, we compared five PARPi with different PARP-trapping capa...Ewing sarcoma (EwS) shows a limited clinical response to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), despite promising preclinical data. In this study, we compared five PARPi with different PARP-trapping capacities in PDX-derived cell lines and mouse models. Talazoparib, the strongest PARP-trapping agent, showed markedly greater efficacy than olaparib or veliparib. It triggered extensive DNA damage, micronuclei formation, and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, leading to robust type I interferon and pro-inflammatory cytokine release, an effect not seen in osteosarcoma. In vivo, talazoparib also reshaped the tumor microenvironment, increasing macrophage infiltration and reducing tumor growth. In vitro, conditioned media from treated EwS cells promoted M0-like macrophage polarization towards an inflammatory M1-like status. These immunostimulatory effects were initiated by tumor-derived interferons and were absent in talazoparib-resistant and olaparib-treated EwS cells, underscoring the importance of the PARP trapping activity of PARPi rather than catalytic inhibition. Combination of talazoparib with exogenous 2'-3'-cyclic GMP-AMP (cGAMP) does not further increase phagocytosis of EwS cells when co-cultured with macrophages, and no additive effects were observed under the tested conditions. Thus, talazoparib is a potent cytotoxic agent with innate immune activation/macrophage-mediated effects, prompting further clinical evaluation in this tumor type.
Zhang W, He B, Zhang L
… +12 more, Li Z, Ma M, Xie J, Wang X, Fang Z, Yue Z, Xue Z, Tang N, Li J, Yin Z, Li Y, Liu Y
Cancer Lett
· 2026 Jun · PMID 42379262
·
Publisher ↗
Biliary tract cancers (BTCs) comprise biologically heterogeneous subtypes with limited therapeutic options and variable responses to sorafenib. The biological basis underlying this variability remains unclear. In this st...Biliary tract cancers (BTCs) comprise biologically heterogeneous subtypes with limited therapeutic options and variable responses to sorafenib. The biological basis underlying this variability remains unclear. In this study, we compared intrahepatic cholangiocarcinoma (iCCA) and gallbladder cancer (GBC) models under defined sorafenib exposure conditions using transcriptomic profiling, Seahorse based mitochondrial stress assays, pharmacologic combination analysis, and patient-derived organoid models. In representative iCCA models, 1.25 μM sorafenib increased mitochondrial respiration and ATP production, whereas at 10 μM suppressed this respiratory adaptation. In contrast, representative GBC models exhibited persistent suppression of mitochondrial respiratory function across the tested conditions and did not display a comparable concentration-dependent shift. Integrated transcriptomic and pharmacologic analyses further identified mitochondrial Complex I as a treatment relevant vulnerability under sorafenib exposure, with stronger combination interactions observed in iCCA models. These findings indicate that iCCA and GBC differ in their metabolic responses to sorafenib and highlight subtype specific differences in mitochondrial adaptation under treatment stress.
Huang X, Hu W, Wu Y
… +24 more, Zhu Q, Song G, Liu M, Wu S, Yin L, Wang Y, Wu P, Xu D, Lyu N, Wang Q, Tian L, Zhang K, Lu Z, Chen J, Guo F, Wei J, Xiao B, Wu J, Gao W, Feng X, Mou Y, Lin J, Tu M, Jiang K
Cancer Lett
· 2026 Jun · PMID 42379261
·
Publisher ↗
Ampullary adenocarcinoma (AMPAC) is a rare and heterogeneous malignancy with markedly variable clinical outcomes, underscoring the urgent need for molecularly informed classification and personalized therapeutic strategi...Ampullary adenocarcinoma (AMPAC) is a rare and heterogeneous malignancy with markedly variable clinical outcomes, underscoring the urgent need for molecularly informed classification and personalized therapeutic strategies. Current AMPAC classification relies primarily on morphological and immunohistochemical criteria, which lack prognostic accuracy and fail to capture the underlying molecular and tumor microenvironment heterogeneity. In this study, we integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and clinicopathological data to elucidate the molecular architecture of AMPAC and introduced a transcriptomic-based molecular classification (AMS). The AMS categorized patients into two molecular subtypes: mesenchymal AMPAC (AMS-M) and classical AMPAC (AMS-C). The AMS-M demonstrated increased epithelial-mesenchymal transition (EMT) and stromal activation, correlating with basal-like subtypes associated with unfavorable prognosis. In contrast, AMS-C tumors exhibited metabolic and differentiation programs with relatively preserved immune infiltration. Importantly, we identified MUC16 as a pivotal biomarker specifically overexpressed in AMS-M tumors. MUC16 knockout markedly reversed EMT, attenuated invasive and migratory capacities, and restored chemosensitivity in both cell lines and their xenograft models. Collectively, our findings establish AMS as a prognostically and therapeutically informative molecular classification framework for AMPAC, unveil the critical role of the tumor microenvironment in AMPAC heterogeneity, and provide a translational foundation for precision oncology in this rare tumor.
Yi Y, Lai J, Jian L
… +3 more, Tian Y, Zhang X, Zhang R
Cancer Lett
· 2026 Jun · PMID 42372903
·
Publisher ↗
Cancer therapy resistance remains a major barrier to durable clinical benefit across chemotherapy, targeted therapy, cell-cycle-directed therapy, and immunotherapy. Although genetic alterations and epigenetic rewiring ha...Cancer therapy resistance remains a major barrier to durable clinical benefit across chemotherapy, targeted therapy, cell-cycle-directed therapy, and immunotherapy. Although genetic alterations and epigenetic rewiring have long been recognized as major contributors to treatment failure, increasing evidence indicates that post-transcriptional regulation by the epitranscriptome represents an additional and highly dynamic layer of adaptive resistance. Among RNA modifications, N6-methyladenosine (m6A) has emerged as the most abundant internal modification in eukaryotic mRNA and a pivotal regulator of cancer progression, immune remodeling, and therapeutic response. Accumulating studies show that dysregulated m6A writers, erasers, and readers promote resistance by sustaining cellular plasticity and stemness, rewiring glucose and amino acid metabolism, reinforcing redox buffering and ferroptosis suppression, reshaping autophagy and mitochondrial homeostasis, and enhancing DNA damage repair and RNA processing programs. Beyond tumor-intrinsic survival, m6A also modulates immune escape by altering checkpoint responsiveness, immunometabolic suppression, and tumor-microenvironment communication. Recent advances have further expanded the conceptual framework of the field, revealing noncanonical functions of m6A regulators in adaptive translation, biomolecular condensate formation, and crosstalk with post-translational modifications such as lactylation. These findings position the m6A epitranscriptome not merely as a regulator of RNA fate, but as a systems-level coordinator of therapy-adaptive tumor states. In this review, we summarize current progress in understanding how m6A drives cancer therapy resistance across distinct therapeutic contexts, highlight emerging mechanistic frontiers, and discuss the translational potential and current challenges of targeting m6A regulators for overcoming resistant disease.
Cancer Lett
· 2026 Jun · PMID 42372590
·
Publisher ↗
Recurrent glioblastoma (rGBM) exhibits aggressive progression and therapeutic resistance. However, how mechanical cues within the tumor microenvironment contribute to stemness and chemoresistance through mechanotransduct...Recurrent glioblastoma (rGBM) exhibits aggressive progression and therapeutic resistance. However, how mechanical cues within the tumor microenvironment contribute to stemness and chemoresistance through mechanotransductive and epigenetic regulation remains incompletely understood. GBM tissues and derived cell models were systematically characterized to examine how defined matrix mechanical conditions are associated with stemness and chemoresistance. Multivalent VCAM1-Fc decoys were engineered to modulate ITGA4-associated mechanosensing, and mechanistic pathways connecting metabolism to mechanotransduction were interrogated using targeted perturbations. rGBM tissues exhibited elevated stiffness and extracellular matrix (ECM) remodeling, which were associated with enhanced stemness and temozolomide resistance alongside increased H3K18 histone lactylation. Stiffness-associated temozolomide (TMZ) resistance manifested as a pre-activated resistance state prior to TMZ exposure and a shielding effect under high-stiffness conditions that further attenuated TMZ efficacy. ITGA4 was identified as a mechanosensing-associated node, and engineered multivalent VCAM1-Fc decoys mediated valency-dependent, reversible competitive inhibition at cell-surface ITGA4, attenuating mechanosensing-associated stemness and chemoresistance without inducing non-specific cytotoxicity. ECM stiffening is linked to stemness maintenance and temozolomide resistance in recurrent GBM through H3K18la-associated epigenetic regulation, while ITGA4/YAP-related mechanosensing provides a membrane-proximal axis that can be attenuated by multivalent VCAM1-Fc. Multivalent VCAM1-Fc may therefore reduce stiffness-associated malignant phenotypes by limiting ITGA4-dependent mechanotransduction.
Cancer Lett
· 2026 Jun · PMID 42365891
·
Publisher ↗
The design of antigen-binding domains (binders) is emerging as a decisive frontier in chimeric antigen receptor (CAR)-T cell engineering. Rather than serving as passive recognition elements, binders actively shape antige...The design of antigen-binding domains (binders) is emerging as a decisive frontier in chimeric antigen receptor (CAR)-T cell engineering. Rather than serving as passive recognition elements, binders actively shape antigen selectivity, signaling thresholds, exhaustion propensity, persistence, and toxicity. We propose that optimal CAR performance requires a multidimensional design strategy. Success cannot be achieved by maximizing a single variable like affinity. Designers must instead integrate epitope position, binding kinetics, avidity, molecular geometry, and biophysical stability. In this review, we synthesize recent advances showing how these parameters collectively govern immunological synapse formation, antigen-density discrimination, and functional durability. Importantly, we highlight that the consequences of binder design are increasingly evident not only in mechanistic and preclinical studies, but also in real-world clinical translation and commercial trajectories. We further examine how the binder landscape has expanded beyond conventional scFvs to include VHHs, monobodies, DARPins, D-domains, peptides, natural ligands, TCR-mimic binders, and de novo AI-designed proteins. Together, these advances support a shift from empirical binder selection to rational binder orchestration as a foundational principle for next-generation CAR-T immunotherapy.
Terada T, Suzuki T, Ohnuki K
… +13 more, Yoshikawa T, Shimomura M, Shoda K, Amaishi Y, Takeichi K, Kudo M, Sugimoto M, Kobayashi S, Takenouchi K, Tsukamoto N, Gotohda N, Okamoto S, Nakatsura T
Cancer Lett
· 2026 Jun · PMID 42362103
·
Publisher ↗
Glypican-3 (GPC3) is highly expressed in most hepatocellular carcinomas (HCCs) and hepatoblastoma, shows minimal expression in non-tumor adult tissues, and is also detected in several other malignancies, making it an ide...Glypican-3 (GPC3) is highly expressed in most hepatocellular carcinomas (HCCs) and hepatoblastoma, shows minimal expression in non-tumor adult tissues, and is also detected in several other malignancies, making it an ideal target for anticancer immunotherapy. We previously demonstrated in clinical trials that GPC3 peptide vaccination can induce durable antitumor immunity in patients with HCC and pediatric hepatoblastoma and established human leukocyte antigen (HLA)-A∗02:01-restricted GPC3-specific cytotoxic T lymphocyte (CTL) clones. In this study, we isolated high-avidity T-cell receptors (TCRs) from CTL clones established from a pediatric hepatoblastoma patient who achieved long-term recurrence-free survival for more than 10 years after surgical resection of pulmonary metastases followed by GPC3 peptide vaccination. Using a retroviral vector incorporating endogenous TCR suppression, these TCR genes were introduced into primary human T cells to generate GPC3-specific TCR-engineered T cells (TCR-T cells). These TCR-T cells exhibited GPC3-specific recognition and significant cytotoxicity against GPC3-positive tumor cells in vitro, while showing minimal activity against GPC3-negative targets. Moreover, GPC3-specific TCR-T cells migrated to tumor sites, resulting in the prevention of tumor engraftment as well as tumor growth suppression and stabilization in xenograft models. GPC3-targeted TCR-T cells derived from CTLs induced by GPC3 peptide vaccination demonstrated potent antitumor activity against HLA-A∗02-positive and GPC3-positive cancers. These findings provide an important rationale for Phase I clinical trials of GPC3-targeted TCR-T cells as a promising therapeutic strategy for GPC3-expressing solid tumors, including HCC and refractory hepatoblastoma.
Bai F, Qin G, Li J
… +5 more, Zhan W, Fu Y, Wu Z, Cheng Y, Deng Y
Cancer Lett
· 2026 Jun · PMID 42362102
·
Publisher ↗
Oncolytic virotherapy has emerged as a promising strategy for cancer immunotherapy; however, its immunomodulatory mechanisms in colorectal cancer remain incompletely understood. Here, we evaluated the therapeutic effects...Oncolytic virotherapy has emerged as a promising strategy for cancer immunotherapy; however, its immunomodulatory mechanisms in colorectal cancer remain incompletely understood. Here, we evaluated the therapeutic effects of the oncolytic virus VG161 in murine colorectal cancer models (CT26.WT and MC38) and systematically characterized the associated tumor microenvironment (TME) remodeling. Using single-cell RNA sequencing, flow cytometry, and multiplex immunohistochemistry, we identified a distinct population of CD3 macrophages that was markedly expanded following VG161 treatment. Functional analyses suggested that these cells exhibit enhanced phagocytic capacity and immunostimulatory properties, including the recruitment of CCL5 CD8 effector memory T cells (Tem). Mechanistically, VG161-infected tumor cells were found to secrete complement-related factors, including complement factor B (CFB) and complement component 3 (C3), which may contribute to CD3 upregulation and the emergence of a CD3 macrophage-associated state. These findings suggest that complement signaling may contribute to CD3 upregulation in macrophages, although the downstream mechanisms remain to be elucidated. Furthermore, VG161 treatment enhanced systemic antitumor immunity and improved responsiveness to immune checkpoint blockade. Collectively, these findings reveal a potential role for VG161 in orchestrating innate-adaptive immune interactions and provide a rationale for targeting macrophage-mediated pathways to improve colorectal cancer immunotherapy.
Rilee GJ, Zaman SU, Manupati K
… +8 more, Ma Z, Hoyle RG, Bacolod MD, Lopresti MQ, Brown AM, Das SK, Fisher PB, Li J
Cancer Lett
· 2026 Jun · PMID 42342022
·
Publisher ↗
Melanoma differentiation associated gene-9 (MDA-9), also known as Syntenin-1 or SDCBP, exhibits elevated expression in multiple cancers, promoting invasion, migration, and tumor cell survival. The TCGA database reveals h...Melanoma differentiation associated gene-9 (MDA-9), also known as Syntenin-1 or SDCBP, exhibits elevated expression in multiple cancers, promoting invasion, migration, and tumor cell survival. The TCGA database reveals high MDA-9 expression in late-stage HPV (-) HNSCC tissues, which associates with poor patient survival. Moreover, bioinformatics analyses support a potential role of MDA-9 in promoting cancer stemness in HNSCC tissues. We characterized the functional role of MDA-9 in HNSCC tumorigenesis, particularly in relation to cancer stem cell maintenance. Knockdown of MDA-9 suppresses BMI1, a functional cancer stem cell marker in HNSCC, and the self-renewal of cultured HNSCC cells. Mechanistically, MDA-9 controls expression of BMI1 through NF-κB p65. Targeting MDA-9 with a specific small molecule pharmacological inhibitor, IVMT-Rx-4, inhibits HNSCC growth and metastasis in a HNSCC xenograft mouse model. In vivo lineage tracing reveals that IVMT-Rx-4 potently inhibits self-renewal and tumorigenicity of Bmi1 cancer stem cells in a spontaneous model of HNSCC. Additionally, IVMT-Rx-4 significantly improves treatment with cisplatin by eliminating cisplatin-enriched Bmi1 cancer stem cells, thereby overcoming cisplatin resistance. Taken together, our results demonstrate that targeting MDA-9 with IVMT-Rx-4 is an effective strategy for treating HNSCC by eliminating cancer stem cells, and IVMT-Rx-4 is a promising chemical entity that may be amenable for developing an effective therapy for HNSCC.