Aim: Hepatocellular carcinoma (HCC) remains a formidable worldwide health challenge, characterized by inadequate treatment efficacy and unsatisfactory clinical prognosis. Our previous study implicated LINC01607 in lenvatinib resistance, but its role in HCC progression and ferroptosis-associated vulnerability remains unclear. Methods: LINC01607 expression was examined in HCC patient samples and The Cancer Genome Atlas datasets. Cellular, animal, and patient-derived organoid (PDO) models were used to evaluate its biological function. RNA sequencing, ferroptosis-related assays, rescue experiments, and drug-sensitivity analyses were performed to explore associated downstream pathways. Results: LINC01607 was upregulated in HCC tissues and associated with aggressive clinicopathological features and poor survival. Functional assays showed that LINC01607 promoted HCC cell proliferation, migration, invasion, tumor growth, and metastasis. LINC01607 depletion induced ferroptosis-associated changes, including increased lipid peroxidation, glutathione depletion, and Fe2+ accumulation under ferroptotic stress, which were partially reversed by ferroptosis inhibitors. LINC01607 knockdown also enhanced sensitivity to RSL3 and sorafenib, while ferrostatin-1 partially rescued the increased sorafenib sensitivity. RNA sequencing and rescue experiments suggested involvement of the p62-Keap1-Nrf2 pathway. LINC01607 depletion was associated with reduced SQSTM1/p62, Nrf2, and ferroptosis-resistance proteins, whereas p62 overexpression partially reversed these effects and Nrf2 knockdown abrogated the rescue. In xenograft and PDO models, LINC01607 depletion improved the response to sorafenib. Conclusion: LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62-Keap1-Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.
Therapeutic resistance represents a formidable bottleneck in colorectal cancer (CRC) management, severely limiting the clinical efficacy of both conventional regimens and novel immunotherapies. Emerging evidence underscores tertiary lymphoid structure (TLS) - ectopic lymphoid aggregates newly sculpted within the tumor microenvironment (TME) - as pivotal orchestrators of localized antitumor immunity and prime therapeutic targets to circumvent resistance. Distinct from secondary lymphoid organs, TLS facilitate in situ immune cell priming, clonal expansion, and functional differentiation, thereby sustaining a robust adaptive immune response. This review systematically dissects the cellular architecture, maturation dynamics, and spatial heterogeneity of TLS in primary and metastatic CRC, clarifying how these attributes dictate clinical outcomes and treatment responsiveness. Mechanistically, we delineate the molecular networks driving TLS neogenesis, encompassing chemokine cascades, tumor necrosis factor (TNF) superfamily signaling, and interactive crosstalk with the gut microbiota. Furthermore, we summarize cutting-edge preclinical strategies - including stimulator of interferon genes agonists, bio-nanovaccines, and hypofractionated radiotherapy combinations - engineered to trigger TLS neogenesis, promote germinal center (GC) maturation, and enrich stem-like effector tumor-infiltrating lymphocytes (TILs) to convert immunologically “cold” tumors into “hot” niches. By integrating mechanistic paradigms with clinical applications, this review provides a definitive framework for leveraging TLS targeting as a transformative modality to modulate drug resistance and optimize therapeutic trajectories in CRC; the graphical abstract is shown below.
Aim: Colorectal cancer (CRC) ranks among the most prevalent malignancies across the globe, with treatment resistance often closely linked to the complexity of the tumor microenvironment (TME). This study aims to establish a gene signature associated with epithelial-mesenchymal transition (EMT) that integrates TME dynamics, prognosis prediction, and drug resistance assessment in CRC. Methods: We employed the Cancer Genome Atlas (TCGA) resource and bulk RNA-sequencing profiles linked to EMT to identify common differentially expressed genes (DEGs). An eight-gene signature was constructed using multivariable Cox regression analysis. The correlations of risk groups (scores) with overall survival, biological characteristics, and drug sensitivity were analyzed in CRC patients. Results: Patients in the high-risk group exhibited significantly worse clinical outcomes than those in the low-risk group. Moreover, a lower risk score was significantly correlated with increased responsiveness to both immune checkpoint inhibitors and 5-fluorouracil in CRC patients. Additionally, experiments in vitro and in vivo confirmed that FABP4 functions as an oncogene in CRC by facilitating cell growth, migration, and chemotherapy resistance. Conclusion: The EMT-associated gene signature holds significant value for predicting clinical prognosis, immunotherapy responsiveness, and chemotherapy sensitivity in CRC.
Aim: Malignant pleural mesothelioma (MPM) is a paradigmatic inflammation-associated cancer and a major therapeutic challenge due to its resistance to treatment. Inflammation is thought to promote both tumor progression and therapy resistance. Senescence-associated secretory phenotype (SASP)-mediated, chemotherapy-induced release of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) contributes to pemetrexed resistance in MPM cells in vitro. Methods: Pro-inflammatory mediators (PIMs) and specialized pro-resolving mediators (SPMs) were quantified in pleural exudates using liquid chromatography-tandem mass spectrometry. Single-cell RNA-sequencing datasets were analyzed to assess the distribution of SPM-producing enzymes between mesothelial and mesothelioma cells in both tumor tissue and uninvolved pleura. Least Absolute Shrinkage and Selection Operator regression (LASSO) was used to derive a composite prognostic score (CPS) from SPM-related gene expression. Results: Chemotherapy-treated patients exhibited a reduction in SPMs - including resolvins, protectins, and maresins - alongside increased prostaglandin levels. Single-cell analysis revealed differential partitioning of SPM-producing enzymes, with lower expression in mesothelioma cells compared with mesothelial cells. A five-gene CPS derived from this lipid mediator landscape independently predicted overall survival beyond conventional clinical parameters. Conclusion: Chemotherapy alters the lipid mediator composition of pleural exudates in MPM by reducing SPMs, thereby disrupting resolution pathways. This effect is consistent with an intrinsic imbalance in expression between mesothelial and mesothelioma cells. Together, these findings suggest that impaired resolution of inflammation contributes to a pro-tumorigenic, pro-inflammatory, and chemoresistant microenvironment in MPM, with potential prognostic implications.
Tumors are highly dynamic diseases characterized by significant heterogeneity. They consist of multiple cellular populations with distinct properties that respond differently to therapeutic pressure. This heterogeneity may arise from spatial variation across tumor regions (spatial heterogeneity) as well as from temporal changes during tumor evolution and treatment (temporal heterogeneity). As a consequence, drug-resistant subclones often emerge under therapy and contribute to treatment failure. Advances in single-cell and spatial multi-omics technologies enable precise quantification of tumor heterogeneity, supporting detailed investigation of how heterogeneity contributes to chemoresistance and informing the development of personalized therapeutic strategies. In this review, we summarize the evolutionary dynamics underlying the emergence of tumor drug resistance and examine the molecular mechanisms responsible for failure of targeted therapies. We highlight how advances in single-cell and spatial multi-omics have significantly improved our ability to elucidate these processes. We further suggest that addressing tumor drug resistance may require a shift from static, single-target approaches toward dynamic, biology-informed personalized strategies. Integrating high-resolution multi-omics monitoring with functional validation could enable identification of subclonal vulnerabilities, support adaptive treatment adjustment, and contribute to more durable clinical responses.
Aim: Cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) display high metabolic plasticity, supporting tumor aggressiveness and therapeutic resistance. Here, we investigated the role of the mitochondrial chaperone TRAP1 in regulating mitochondrial architecture, metabolism, and adhesion in CSCs. Methods: We studied an in vitro model of CSCs using Panc1 cells and the corresponding stable TRAP1-knockout cells (TRAP1-KO). Molecular techniques used were quantitative polymerase chain reaction (qPCR), Western blot, transmission electron microscopy, and Seahorse technology. Results: CSCs showed increased TRAP1 expression after 2 weeks of culture, reflecting a preferential metabolic shift toward glycolysis. TRAP1 deletion impaired the ability of CSCs to form compact spheroids without altering canonical CSC traits, such as reduced proliferation, increased stem marker expression, and enhanced chemoresistance. We demonstrate that TRAP1 deletion increases CDH1, an effect that was reversed by succinate supplementation, indicating that the TRAP1-succinate-CDH1 axis controls adhesion-related properties. Ultrastructural analyses revealed profound mitochondrial remodeling in the absence of TRAP1: parental cells displayed enlarged, elongated mitochondria with wider cristae, whereas CSCs developed fragmented mitochondria with thinner cristae and tighter crista junctions. These alterations were closely associated with the differential regulation of mitochondrial fission factor (MFF). Functionally, loss of TRAP1 enhanced oxidative phosphorylation, leading to increased mitochondrial adenosine triphosphate (ATP) production, elevated maximal respiration, and reduced proton leak. Conclusion: Collectively, these findings identify TRAP1 as a critical regulator of mitochondrial organization, respiratory efficiency, and CDH1-mediated adhesion in PDAC CSCs, highlighting metabolic and structural vulnerabilities that may be exploited therapeutically to destabilize CSC homeostasis and enhance treatment response.
Recently, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have achieved major breakthroughs in oncology, with 32 drugs approved over the past decade. This advancement has established immunotherapy as the fifth major antitumor modality following surgery, chemotherapy, radiotherapy, and targeted therapy. However, PD-1/PD-L1 inhibitors induce sustained responses in only a limited number of patients, and primary and acquired resistance remain critical challenges in clinical practice. As understanding of the complex crosstalk among cancer cells, the tumor microenvironment, and the host immune system deepens, numerous strategies to overcome PD-1/PD-L1 inhibitor resistance have been proposed. In this review, we examine the current development of PD-1/PD-L1 inhibitors, analyze global approval trends, and evaluate their monotherapy efficacy across various tumor types. As multi-target combination therapy is an essential strategy for overcoming resistance, we analyze key combination targets - such as vascular endothelial growth factor (VEGF), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3) - and highlight the clinical success of novel dual-target regimens such as ivonescimab (PD-1/VEGF). Furthermore, we discuss potential approaches to overcoming resistance from both microenvironmental (e.g., targeting cancer-associated fibroblasts or utilizing antibody-drug conjugates) and macroenvironmental (e.g., modulating the microbiota or sex hormones) perspectives. This review provides a forward-looking framework for designing precision- and mechanism-driven combination therapies aimed at converting non-responders into responders.
Aim: Clear cell renal cell carcinoma (ccRCC) presents an "immune paradox" where high CD8+ T cell infiltration correlates with poor survival and limited response to immune checkpoint blockade (ICB). Simple cell density metrics fail to capture the functional state of the immune microenvironment, suggesting an uncharacterized spatial mechanism underlying immune evasion and poor clinical outcomes. We aimed to develop an AI-driven spatial proteomics framework to decode this immunosuppressive phenotype. Methods: We developed PhenoSSP, a hierarchical deep learning framework based on a Vision Transformer backbone, designed for single-cell phenotyping from 7-channel multiplex immunofluorescence (mIF) images. It was applied to 1,633 tissue microarray (TMA) cores from 834 ccRCC patients. We defined a density-normalized Spatial Interaction Score was defined to quantify FOXP3+ regulatory T cell (Treg) enrichment within a 30 μm radius of CD8+ T cells. Survival analyses were performed using Kaplan-Meier curves with log-rank tests and multivariable Cox regression models. Results: PhenoSSP achieved a balanced accuracy of 71.0% and an F1-Macro of 70.7%, outperforming conventional methods. CD8+ T-cell density alone was not significantly associated with overall survival (OS, P = 0.057), whereas the Spatial Interaction Score was significantly associated with poor OS (log-rank test, P = 0.012) and was significantly higher in non-survivors (P = 0.032). Conclusion: This study reveals a spatial basis for immune evasion and poor prognosis in ccRCC: the pre-existing Treg enrichment near CD8+ T cells, rather than the abundance of effector cells, was associated with impaired antitumor immunity. The Spatial Interaction Score serves as a candidate prognostic biomarker and provides a rationale for Treg-targeting combination strategies in patients harboring spatially defined suppressive niches.
The reciprocal feedback between cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs) is increasingly recognized as a driver of therapeutic resistance and tumor evolution. According to the "soil and seed" hypothesis, CAFs create a biochemical and biomechanical "soil" for CSCs to seed, grow, and thrive. In turn, CSCs manipulate and transform fibroblasts to promote CSC traits, thus completing the loop of CAF-CSC crosstalk through bidirectional molecular communication within the tumor microenvironment. This review encompasses recent advances in CAF heterogeneity, including conserved and malignancy-specific subtypes, as well as the molecular dialogue driving resistance. We also briefly discuss emerging therapeutic approaches, particularly the potential of natural compounds to target both CSCs and CAFs. By bridging mechanistic insights with translational innovations, this review provides a roadmap for breaking the CSC-CAF alliance, offering hope for overcoming therapeutic resistance and improving cancer outcomes.
Aim: Cisplatin resistance remains a major obstacle to the effective treatment of tongue squamous cell carcinoma (TSCC). This study is dedicated to elucidating the role and mechanism of circular RNA (circRNA) hsa-circ-0001030 in modulating cisplatin sensitivity and metabolic reprogramming in TSCC. Methods: CircRNA sequencing, quantitative polymerase chain reaction, and RNA fluorescence in situ hybridization were used to test hsa-circ-0001030 expression in TSCC tissues and cell lines. Gain-of-function assays (colony formation, cell counting kit-8, Transwell assay, and xenograft models) were conducted to evaluate proliferation, invasion, and cisplatin response. Mechanistic studies, including RNA pull-down, RNA-binding protein immunoprecipitation, and western blotting, were performed to identify pyruvate kinase M2 (PKM2) as a binding partner of hsa-circ-0001030 and to assess glycolytic activity, glucose uptake, and lactate production. Results: Hsa-circ-0001030 was markedly downregulated in TSCC and cisplatin-resistant cells. Overexpression of hsa-circ-0001030 suppressed tumor growth, migration, and glycolytic flux, while enhancing cisplatin sensitivity both in vitro and in vivo. Mechanistically, hsa-circ-0001030 directly bound to PKM2 at nucleotides 138-169, inhibited PKM2 enzymatic activity, restraining tetramer formation and increased tyrosine 105 (Tyr105) phosphorylation and thereby blocking PKM2-driven glycolysis. Clinically, low hsa-circ-0001030 expression correlated with advanced tumor-node-metastasis stage, poor differentiation, and unsatisfying prognosis in TSCC patients. Conclusion: Hsa-circ-0001030 acted as a tumor-suppressive circRNA that might depress PKM2-dependent metabolic reprogramming and cisplatin resistance in TSCC, highlighting its potential as a prognostic biomarker and therapeutic target for overcoming chemoresistance.
Aim: Antibody-drug conjugates (ADCs) feature an antibody recognizing a specific protein joined to a potent toxic payload. Numerous ADCs have received U.S. Food and Drug Administration (FDA) approval; however, clinical resistance arises. Resistance mechanisms include decreased expression or mutation of the antibody target, impaired payload release, or increased expression of adenosine triphosphate (ATP)-binding cassette (ABC) efflux transporters associated with multidrug resistance. We therefore sought to characterize the interactions of ABC multidrug transporters with ADC payloads. Methods: We performed a high-throughput screen with 27 common ADC payloads using cell lines expressing ABC transporters P-glycoprotein [P-gp, encoded by ABC subfamily B member 1 (ABCB1)] or ABC subfamily B member G2 (ABCG2, encoded by ABCG2). Confirmatory assays were also performed using cells transfected to express P-gp, ABCG2, or multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1). Results: Several commonly used ADC payloads were substrates of P-gp, including calicheamicin γ1, monomethyl auristatin E, mertansine (DM1), and ravtansine (DM4). All the pyrrolobenzodiazepines tested - SJG136, SGD-1882, SG2057, and SG3199 - were substrates of P-gp, ABCG2, and MRP1. The modified anthracyclines nemorubicin and its metabolite PNU-159682 were poorly transported by both ABCB1 and ABCG2 and displayed nanomolar to picomolar toxicity. Further, we found that the efficacy of the FDA-approved ADC mirvetuximab soravtansine, with DM4 as the toxic payload, was decreased in cell lines expressing P-gp. In contrast, Duocarmycin DM and PNU-159682 were exquisitely toxic to a panel of 99 cancer cell lines of varying origins. Conclusion: Several commonly used ADC payloads can be transported by ABC transporters, potentially leading to transporter-mediated drug resistance in patients. Future ADCs should be developed using payloads that are not ABC transporter substrates.
Cancer therapy remains an active field of investigation, particularly in understanding and overcoming therapy resistance. Small non-coding RNAs, such as microRNAs (miRNAs), are emerging as key regulators of cancer survival, progression, proliferation, invasion, migration, and metastasis. Although many studies have linked miRNAs to cancer therapy outcomes, significant questions remain regarding their precise molecular and cellular roles in therapy resistance. Increasing evidence shows that miRNAs influence critical pathways such as apoptosis, immune evasion, and other signaling cascades. However, there have been many setbacks because of the limitations in knowledge of each specific miRNA's function. A deeper understanding of miRNA expression and function may enhance the development of more effective cancer therapeutics and improve overall survival of patients. This review explores the role of miRNA expression as a key regulator of therapeutic resistance in cancer patients.
Non-small-cell lung cancer (NSCLC) remains the leading cause of global cancer-related mortality. NSCLC patients with epidermal growth factor receptor (EGFR) mutations benefit substantially from treatment with EGFR tyrosine kinase inhibitors, particularly osimertinib. Although recent clinical trials have established osimertinib as effective treatment across many stages of EGFR-mutant NSCLC, the inevitable emergence of acquired resistance poses a major therapeutic challenge despite the substantial clinical benefit. Understanding the mechanisms of osimertinib acquired resistance is urgently needed to identify effective strategies to overcome it. Resistance to osimertinib including on-target mechanisms such as novel EGFR secondary mutation, off-target mechanisms such as mesenchymal-epithelial transition or human EGFR 2 amplification, mutations in downstream signaling molecules, and oncogenic fusions, and the Histological transformations (such as epithelial-mesenchymal transition, squamous cell carcinoma, or small cell lung cancer) have been well described. This review summarizes the mechanisms and clinical significance of osimertinib-acquired resistance in recent years, as well as new clinical treatments. It is expected to provide valuable insights and potential new strategies for the clinical treatment of EGFR-mutated NSCLC patients with osimertinib resistance.
Head and neck squamous cell carcinoma (HNSCC), which arises from the mucosal linings of the oral cavity, pharynx, and larynx, represents the most prevalent head and neck malignancy. This cancer is notable for its elevated incidence and substantial mortality. The intricate anatomy of the region contributes to marked tumor heterogeneity, rendering the pursuit of effective therapeutic regimens a crucial aspect of enhancing clinical outcomes. Recently, the advent of immune checkpoint blockade, particularly agents targeting programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4, has introduced significant advancements within the oncological landscape, including for HNSCC. The introduction of immune checkpoint inhibitors, specifically the PD-1 blockers pembrolizumab and nivolumab, has established a new therapeutic standard for recurrent/metastatic HNSCC (R/M HNSCC). However, the clinical benefit is not universal, as a primary challenge remains the high incidence of treatment resistance. Consequently, a majority of patients (approximately 60%-70%) with R/M HNSCC derive minimal or no benefit from this form of immunotherapy, highlighting the critical need to understand the underlying resistance mechanisms. This review comprehensively discusses the types of immunotherapy resistance in HNSCC and the underlying mechanisms contributing to resistance. Furthermore, it reviews current strategies to overcome immunotherapy resistance, providing new perspectives for improving therapeutic efficacy in HNSCC.
Rhabdomyosarcomas (RMS) are aggressive pediatric soft tissue tumors. The fusion-negative subtype (FN-RMS) is characterized by RAS pathway mutations and genomic instability. While standard chemotherapies - vincristine, actinomycin D, and alkylating agents - are effective against localized disease, multidrug resistance (MDR) often leads to treatment failure in relapsed and metastatic RMS. Key drivers of MDR in FN-RMS include dysregulated RAS/PI3K signaling, enhanced DNA repair, evasion of apoptosis, and alterations in drug transport and metabolism. Preclinically, vertical inhibition of the RAS/MAPK and PI3K/AKT/mTOR pathways shows promise but is limited by toxicity and compensatory feedback. Combination strategies targeting MEK, IGF1R, and PI3K, as well as epigenetic regulators and metabolic pathways, demonstrate synergistic effects. BH3 mimetics can restore apoptotic sensitivity, especially in FBW7-deficient tumors. Radiotherapy resistance is mediated through the DNA-PK–mTORC2–AKT axis, while drug transporters such as ABCB1 and SLC7A11, along with age-dependent CYP enzyme expression, affect drug bioavailability. Targeting these convergent mechanisms offers a promising therapeutic strategy to overcome resistance in FN-RMS.
Heat shock proteins (HSPs) play a critical role in cancer progression and drug resistance by stabilizing oncoproteins, enhancing DNA repair, and modulating apoptosis pathways. In particular, HSP90 and HSP70 have been implicated in maintaining the survival of drug-resistant cancer cells. Consequently, targeting HSPs holds promise in combating drug resistance in cancers. HSP inhibitors induce apoptosis in resistant cancer cells and act as potent chemosensitizers, enhancing the efficacy of chemotherapy, radiotherapy, and targeted therapies. However, despite promising preclinical data, no HSP inhibitors have been approved by the U.S. Food and Drug Administration (FDA) due to toxicity, limited treatment outcomes, or a lack of specificity. In this review, we attempted to provide a brief overview of small-molecule HSP inhibitors, including the medicinal chemistry of geldanamycin derivatives, resorcinol-based compounds, and purine-scaffold inhibitors. We summarized the recent advancements of HSP inhibitors, especially those in clinical trials, their mechanisms of action, and their combinations in overcoming multidrug resistance in cancers. Furthermore, we discussed the current challenges and proposed possible solutions.
Antibody-drug conjugates (ADCs) have emerged as a transformative class in oncology, integrating the target specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads. By harnessing tumor-specific antigen recognition, ADCs enable the selective delivery of chemotherapeutic agents, thereby enhancing therapeutic efficacy while reducing systemic toxicity. Their clinical success across both hematologic malignancies and solid tumors underscores their potential to redefine targeted cancer therapy. However, the clinical durability of ADCs is increasingly undermined by the emergence of diverse resistance mechanisms that diminish their antitumor activity. These mechanisms encompass the entire drug delivery cascade - from reduced or heterogeneous antigen expression and impaired internalization to defective lysosomal trafficking, enhanced drug efflux, and payload detoxification. In addition, adaptive reprogramming of oncogenic signaling pathways and tumor microenvironmental factors can further attenuate ADC cytotoxicity and promote tumor persistence. A comprehensive understanding of the molecular and cellular bases of ADC resistance is essential for sustaining their therapeutic impact. Advances in linker chemistry, innovative payload design, and the development of bispecific or immune-modulating ADCs offer promising strategies to overcome these challenges. Concurrently, the integration of biomarker-driven patient selection and rational combination regimens is poised to enhance treatment precision and delay resistance. Continued mechanistic and translational research will be pivotal to fully realizing the potential of next-generation ADCs in precision oncology.
Aim: This study aimed to elucidate the role of regulator of chromosome condensation 1 (RCC1) in colorectal cancer (CRC) progression, as well as its involvement in chemoresistance. We specifically examined how RCC1 knockdown modulates cellular responses, including cell cycle, apoptosis, and senescence induced by 5-fluorouracil (5-FU) or doxorubicin (Doxo) in both parental and drug-resistant CRC cell lines. Additionally, we assessed the potential of RCC1 inhibition as an adjuvant therapeutic strategy to enhance the efficacy of chemoradiotherapy in CRC. Methods: The expression of RCC1 in colon cancer tissues and corresponding adjacent non-cancerous tissues was evaluated through tissue microarrays, and its correlation with characteristics and patient prognosis was also examined. Subsequently, a series of in vivo and in vitro experiments based on parental and drug-resistant CRC cell lines were conducted to assess the impact of RCC1 knockdown on sensitivity to 5-FU or Doxo. Finally, transcriptomic analysis and subsequent validation assays were performed to explore the underlying molecular mechanisms. Results: RCC1 knockdown significantly enhanced the antitumor efficacy of 5-FU and Doxo in both CRC and drug-resistant CRC cells. In xenograft models, RCC1 knockdown in combination with 5-FU or Doxo suppressed tumor growth with no evident systemic toxicity observed. Transcriptomic profiling and experimental verification revealed that RCC1 knockdown may impair DNA repair by downregulating key repair proteins, thereby leading to more severe and sustained DNA damage. Conclusion: Our results indicate that RCC1 downregulation enhances the responsiveness of both parental and drug-resistant CRC cells to 5-FU and Doxo, highlighting its potential as a therapeutic adjunct to improve clinical outcomes in CRC.
Immune checkpoint inhibitor (ICI) resistance often stems from intratumoral T cell dysfunction. This review focuses on both tumor-intrinsic and tumor-draining lymph node (TDLN)-centric resistance mechanisms. We detail how specific defects within TDLNs - such as impaired dendritic cell migration and the establishment of immunosuppressive niches - initiate and perpetuate systemic immune dysfunction, ultimately leading to ICI resistance. To counter these challenges, we summarize the following TDLN-targeted strategies: (1) remodeling the TDLN immunosuppressive microenvironment to restore effective antigen presentation; (2) expanding the pool of progenitor exhausted T (Tpex) cells, with a focus on their primary reservoir in TDLNs; and (3) developing adoptive cell therapies using TDLN-derived Tpex cells to generate a robust, personalized antitumor response. By repositioning TDLNs as a central therapeutic target, recent findings suggest strategies aiming to overcome resistance at its source and improve ICI clinical outcomes.
Drug resistance remains a significant challenge in achieving successful cancer treatment, often leading to disease recurrence and reduced patient survival. While traditional tissue biopsies provide valuable insights into tumor biology, they are invasive, infrequent, and may fail to capture the full complexity of tumor heterogeneity and dynamic molecular changes. In contrast, liquid biopsy has emerged as a minimally invasive, real-time approach for monitoring tumor evolution through the analysis of circulating biomarkers. Among these biomarkers, circular RNAs (circRNAs) - a distinct class of non-coding RNAs characterized by covalently closed-loop structures - have gained attention due to their remarkable stability, abundance in body fluids, and functional involvement in gene regulation. Increasing evidence supports the role of circRNAs in mediating drug resistance through mechanisms such as inhibition of apoptosis, epithelial-mesenchymal transition, autophagy, and drug efflux, largely via interactions with microRNAs or proteins. Advanced detection methods, including quantitative reverse transcription polymerase chain reaction, droplet digital polymerase chain reaction, and RNA sequencing, combined with computational tools, enable precise profiling of circRNAs in plasma or exosomes. CircRNA-based liquid biopsies offer a dynamic, non-invasive strategy for early detection of therapeutic resistance and may guide personalized treatment decisions. This review highlights the technological advancements, biological relevance, and clinical promise of circRNAs as circulating biomarkers, emphasizing their potential in precision oncology and future collaborative translational applications.
