Molecular Cancer最新文献

{"title":"Spatially organized regulated cell death-immune coupling in solid tumors: integrating spatial omics with actionable regulated cell death biology.","authors":"Jinkang Tong, Dianjie Zeng, Leyi Chen, Chenming Wei, Jiachen Liu, Zebin Deng","doi":"10.1186/s12943-026-02756-w","DOIUrl":"10.1186/s12943-026-02756-w","url":null,"abstract":"<p><p>The therapeutic efficacy of immune checkpoint blockade is frequently compromised by the profound spatial heterogeneity of solid tumors, where distinct ecological niches are associated with different patterns of immune engagement. Spatial omics has substantially refined our understanding of tumor immune topographies. These range from immune-excluded hypoxic and necrotic cores to immune-infiltrated margins enriched with tertiary lymphoid structures (TLS). However, the mechanistic contribution of regulated cell death (RCD) to these spatial domains remains largely unexplored. In this review, we propose the concept of spatially organized RCD-immune coupling as a hypothesis-generating framework. We argue that RCD modalities are not uniformly distributed across tumors, but are influenced by regional microenvironmental constraints, including metabolic zonation, hypoxia, and mechanical stress. Synthesizing emerging evidence, we discuss how apoptosis, necroptosis, pyroptosis, ferroptosis, and PANoptosis may be enriched within distinct tumor niches. We further examine how region-specific release of damage-associated molecular patterns (DAMPs), cytokines, and lipid mediators may be associated with local immune activation, exhaustion, or exclusion. Importantly, we distinguish spatial association from functional causality and emphasize the need for phenotypic validation and perturbation-based studies. This framework positions RCD as a spatially organized component of tumor immune ecology and a basis for future biomarker and therapeutic studies.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial ecotype in tumor immune exclusion: from spatial architecture to therapeutic strategies.","authors":"Ming Ying, Lei Zhang, Mengwei Jia, Xiaofei Sun, Yibo Su, Chengcheng Liu, Ming Gong, Tao Sun, Bin Zhang","doi":"10.1186/s12943-026-02766-8","DOIUrl":"10.1186/s12943-026-02766-8","url":null,"abstract":"<p><p>The tumor microenvironment (TME) exhibits widespread immunophenotypic heterogeneity. Based on the spatial immune contexture, tumor immune profiles can be classified as immune-inflamed, excluded, or desert. Immune-excluded tumors, a distinct tumor immune phenotype, are characterized by the presence of immune cells (especially CD8⁺ T cells) near tumors but a lack of direct physical contact between immune and tumor cells. Accumulating evidence indicates that tumor immune exclusion is a spatially organized and actively maintained microenvironmental state associated with poor prognosis, impaired T cell infiltration, and resistance to immunotherapy. However, the biological mechanisms and spatial profiling underlying this phenotype remain unclear. Advances in spatial omics technologies and analytical tools have enabled the dissection of the complex spatial architecture of immune-excluded tumors. In this review, we describe recent insights into the core cellular subsets and spatial interaction networks of immune-excluded tumors, incorporating the spatial immune contexture, to provide new theoretical foundations and intervention strategies targeting spatial ecotypes to enhance T cell infiltration and sensitize immune-excluded tumors to immunotherapy. Collectively, these findings support a shift from cell-centric models towards ecotype-centered frameworks in which spatially coordinated cellular alliances govern immune accessibility and therapeutic response. Furthermore, we discuss current challenges in this field, including standardization of spatial multi-omics data integration, real-time monitoring of dynamic spatiotemporal evolution, and optimization of clinical translation pathways. Future investigations should incorporate long-term sampling, organoid models, and basket trial designs to enable precise immune-intervention strategies based on spatial ecotypes.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Programmable ZBTB7A RNA N⁶-methyladenosine site-specific demethylation suppresses colorectal cancer liver metastasis.","authors":"Xuena Chen, Shuo Zhao, Bochen Liu, Yujia Fan, Huanlu Qiu, Lingtong Ren, Xinrui Zhang, Shurui Yan, Yachun An, Shirong Li, Jie An, Jinshen Wang, Huili Hu","doi":"10.1186/s12943-026-02772-w","DOIUrl":"10.1186/s12943-026-02772-w","url":null,"abstract":"<p><p>Colorectal cancer liver metastasis (CRLM) is the primary cause of CRC-related mortality, with inevitable chemoresistance to targeted therapies and immunotherapy. N⁶-methyladenosine (m⁶A), as a crucial epigenetic regulator of gene expression and cellular physiology, involved in the pathogenesis of CRLM. Precise manipulation of m⁶A modifications could offer a non-pharmacological precision treatment for many diseases. However, the precise editing of m⁶A modification in regulating CRLM progression remains elusive. Here we integrated multi-omics and identified zinc finger and BTB domain-containing 7A (ZBTB7A) as an m⁶A-modified transcription factor that promoted CRLM. Mechanistically, METTL3-mediated m⁶A modification of ZBTB7A facilitated recognition by the m⁶A reader YTHDF1/3 complex, enhancing its translation and expression. This m⁶A-dependent regulation promoted CRLM progression via activation of the ARHGAP26/Rho GTPase signaling axis. Notably, we applied a targeted RNA m⁶A erasure (TRME) system to achieve site-specific demethylation at a single site (m⁶A_site_411666) within ZBTB7A mRNA, without perturbing m⁶A abundance. Temporal demethylation at this site is sufficient to inhibit the CRC cell migration. This study unveils the critical role of the METTL3/ZBTB7A/ARHGAP26 axis in the process of m⁶A-mediated CRLM and positions m⁶A precise editing as a promising therapy in the preclinical treatment of CRLM.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148830841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial expression of concern: Epigenetic reactivation of estrogen receptor-α (ERα) by genistein enhances hormonal therapy sensitivity in ERα-negative breast cancer.","authors":"Yuanyuan Li, Syed M Meeran, Shweta N Patel, Huaping Chen, Tabitha M Hardy, Trygve O Tollefsbol","doi":"10.1186/s12943-026-02720-8","DOIUrl":"10.1186/s12943-026-02720-8","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The roles of chromatin remodeling and 3D genome organization in cancers: from mechanistic insights to emerging treatment options.","authors":"Chuqiao Luo, Ninglin Xia, Shin Yee Hui, U Sin Wong, Julia Y Tsang, Hong Hu, Chi Man Tsang, Kwok Wai Lo, Peng Sun, Mumin Shao, Suresh K Alahari, Wei Kang, Gary M Tse, Dajiang Guo","doi":"10.1186/s12943-026-02763-x","DOIUrl":"10.1186/s12943-026-02763-x","url":null,"abstract":"<p><p>Chromatin remodeling comprises a set of molecular mechanisms that regulate gene transcription, DNA replication, and DNA repair by altering nucleosome structure. Previous studies have found that chromatin remodelers are heavily mutated in cancer patients, and targeting aberrant chromatin remodeling activities holds great potential for clinical benefit. Despite these promising findings, several significant hurdles remain before this strategy can be successfully transitioned from bench to bedside. The classic concept of chromatin remodeling focuses on the linear 2D chromatin structural level. While the emergence of sophisticated sequencing modalities has underscored the significance of 3D chromatin architecture, the mechanistic underpinnings and broader implications for cancer biology continue to be largely elusive. This review provides a comprehensive synthesis of the mechanisms and functional roles of classical chromatin remodelers within both physiological and neoplastic contexts. Furthermore, we integrate emerging insights regarding the cohesin complex as a primary mediator of three-dimensional (3D) genomic organization. By proposing a hierarchical framework that distinguishes between 'first-level' (classical) and 'higher-order' chromatin remodeling, we aim to provide a more holistic understanding of the integrated regulatory networks governing chromatin architecture. Furthermore, we have systematically cataloged the landscape of therapeutic strategies targeting chromatin remodelers in oncology. By evaluating the divergence between clinically approved therapies and those currently in developmental pipelines, we delineate the primary challenges confronting the field and propose strategic directions for future research. Collectively, we have delineated the multifaceted contributions of chromatin remodeling to cancer progression. The strategic modulation of these remodeling processes represents a vital frontier in the development of novel therapeutic interventions and is likely to emerge as a primary focus for future cancer management strategies.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ecosystem-matched reprogramming of the tumor-immune microenvironment to overcome cancer immunotherapy resistance.","authors":"Xiaodong Wang, Qianqian Wang, Wei Gao, Songjiang He, Di Xiong, Yiping Huang, Bingwen Zou","doi":"10.1186/s12943-026-02748-w","DOIUrl":"10.1186/s12943-026-02748-w","url":null,"abstract":"<p><p>Immune checkpoint blockade has redefined cancer therapy, yet durable responses remain constrained by resistance states that arise from coordinated tumor-cell, immune, stromal, vascular, lymphatic, and metabolic programs rather than from a single defective pathway. This review develops a translational framework in which tumor-intrinsic immune invisibility, myeloid and regulatory lymphocyte suppression, defective dendritic-cell priming, stromal and vascular exclusion, lymphatic control of antigen drainage, metabolic stress, and ILC2/type 2 immune plasticity are interpreted as interdependent ecosystem states. We discuss therapeutic strategies that reprogram these states, including myeloid and Treg modulation, stromal and vascular remodeling, preservation or restoration of productive lymphatic communication, cytokine and metabolic interventions, alternative checkpoint blockade, oncolytic viruses, vaccines, engineered cell therapies, and nanomedicine-enabled local delivery. Emphasis is placed on the lessons of failed or modestly effective trials, which show that biologically plausible interventions often fail when the dominant resistance bottleneck is not defined, tissue target engagement is not verified, or treatment sequence is not matched to the immune architecture of the tumor. We propose that future progress will depend on ecosystem-matched combinations guided by spatial biomarkers, on-treatment pharmacodynamics, and adaptive trial designs capable of linking mechanism to clinical decision-making.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redifferentiation-enabled TSHRCART cells overcome antigen loss in aggressive thyroid cancers.","authors":"Claudia Manriquez-Roman, Elizabeth L Siegler, Justyna J Gleba, Truc N Huynh, Grace E DeFranco, Aylin Alasonyalilar Demirer, Matthew L Pawlush, Michael Redig, Skyeler M Klinge, Long K Mai, James L Miller, Erin E Miller, Brooke L Kimball, Erin E Tapper, R Leo Sakemura, Carli M Stewart, Ismail Can, Olivia L Sirpilla, Jennifer M Feigin, Kun Yun, Omar L Gutierrez-Ruiz, Hong Xia, Mehrdad Hefazi, Kendall J Schick, Ekene J Ogbodo, Gloria Olivier, Yushi Qiu, Robert C Smallridge, Abba Zubair, Han W Tun, John A Copland, Saad S Kenderian","doi":"10.1186/s12943-026-02744-0","DOIUrl":"10.1186/s12943-026-02744-0","url":null,"abstract":"<p><strong>Background: </strong>Antigen loss remains a major barrier to chimeric antigen receptor (CAR) T cell efficacy in solid tumors. In aggressive thyroid cancers, dedifferentiation is accompanied by coordinated loss of lineage-restricted surface antigens, limiting immune recognition.</p><p><strong>Methods: </strong>Thyroid-stimulating hormone receptor (TSHR) expression was assessed on multiple histotypes of thyroid cancer via immunohistochemistry. TSHR-directed chimeric antigen receptor T (CART) cell therapy was assessed against differentiated thyroid cancer subtypes which highly expressed TSHR and dedifferentiated thyroid cancer subtypes which downregulated TSHR in vitro and in xenograft and patient-derived xenograft (PDX) mouse models. MAPK inhibitors were assessed in combination with TSHR-CART cell therapy in dedifferentiated thyroid cancers which downregulated TSHR in vitro and in PDX mouse models.</p><p><strong>Results: </strong>Using TSHR as a clinically relevant antigen target, we demonstrated that pharmacologic tumor redifferentiation can restore target expression and sensitize tumors to CART cell therapy. TSHR-CART cells mediate durable antigen-specific cytotoxicity in TSHRhigh differentiated thyroid cancer models but are limited in TSHRlow dedifferentiated tumors. In patient-derived anaplastic thyroid cancer xenografts, MAPK inhibition restores TSHR expression and converts tumors from CAR-resistant to CAR-responsive. Concurrent redifferentiation therapy and CART cell treatment yields superior tumor control and survival versus monotherapy, without impairing CART cell function.</p><p><strong>Conclusions: </strong>These findings establish tumor redifferentiation as a generalizable strategy to overcome antigen loss and enhance CART cell therapy in thyroid cancer and potentially other solid tumors.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coupling oxidative de-stabilization with immune activation overcomes radioresistance in hepatocellular carcinoma.","authors":"Jiahao Liu, Ze Mi, Hongpei Tan, Junhong Duan, Feilong Huang, Shahan Guo, Yuting Li, Jianmin Wu, Min Yang, Yunjie Liao, Xiaoqian Ma, Qi Liang, Weiwei Zhang, Xiaofei Fan, Pengfei Rong","doi":"10.1186/s12943-026-02729-z","DOIUrl":"https://doi.org/10.1186/s12943-026-02729-z","url":null,"abstract":"<p><strong>Background: </strong>Radioresistance in hepatocellular carcinoma (HCC) is a coordinated adaptive state rather than failure of a single pathway, sustained by reinforced redox buffering and suppressed immune activation. Strategies that intensify radiation damage without disrupting this state have shown limited efficacy. We sought to determine whether radiosensitization can be achieved by destabilizing tumor oxidative homeostasis while restoring immune competence.</p><p><strong>Methods: </strong>A BSA-templated Fe/Mn nanoassembly incorporating the thiol-reactive agent RRX-001 and folate targeting (BFMR-FA) was developed as a multifunctional and MRI-visible platform. Its biological effects were evaluated across radioresistant cellular systems, organoids, and orthotopic tumor models.</p><p><strong>Results: </strong>BFMR-FA shifts the redox equilibrium of tumor cells beyond a recoverable threshold. By depleting glutathione and suppressing the SLC7A11-GPX4 axis, it converts radiation-induced oxidative stress from a transient signal into sustained lipid peroxidation, resulting in convergent ferroptotic and apoptotic cell death. This transition is accompanied by the emergence of immunogenic stress signals and activation of the STING-TBK1-IRF3 pathway, enabling dendritic cell maturation and expansion of cytotoxic T-cell responses. In vivo, these effects translate into near-complete suppression of radioresistant tumor growth with systemic tolerance. The Fe/Mn composition enables direct visualization of intratumoral delivery by T1-weighted MRI.</p><p><strong>Conclusion: </strong>These findings support a model in which radiosensitization is achieved not by amplifying tumor damage alone, but by collapsing the adaptive redox state that constrains it. The resulting oxidative destabilization coupled with immune activation defines an oxidative homeostasis collapse-driven radio-immuno synergy, providing a generalizable framework for overcoming therapeutic resistance in solid tumors.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149270828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trace elements and tumors: homeostatic networks, molecular mechanisms and new horizons for precision intervention.","authors":"Shengxin Zhang, Keqin Tan, Qin Zhang, Yuzhe Zhao, Ziyang Cheng, Xinggang Yang, Jingsi Dong, Jiaming Liu, Xuelei Ma","doi":"10.1186/s12943-026-02754-y","DOIUrl":"https://doi.org/10.1186/s12943-026-02754-y","url":null,"abstract":"<p><p>Trace elements including iron, copper, zinc, selenium, and manganese are indispensable for life, serving as enzyme cofactors, structural components, and signaling molecules that govern energy metabolism, redox balance, and genomic stability. Their physiological functions exhibit a characteristic dose-effect biphasicity, wherein homeostatic imbalance can both safeguard health and promote malignant transformation. This review systematically delineates the complete lifecycle of these five core trace elements under physiological conditions, emphasizing their extensive functional interconnections, and elucidates how tumor cells hijack this regulatory network through an element-addiction mechanism. We detail the emerging roles of iron-dependent ferroptosis and copper-dependent cuproptosis, alongside the context-dependent regulation of apoptosis and autophagy by trace elements, revealing tumor-specific metabolic vulnerabilities. Within the tumor immune microenvironment, we examine how zinc, iron, copper, selenium, and manganese function as molecular switches: zinc and selenium generally support antitumor immunity, whereas iron and copper dysregulation drives immunosuppressive polarization; manganese additionally emerges as a cGAS-STING agonist with immunotherapeutic potential. In tumor angiogenesis and metastasis, we explore the central roles of copper and iron in extracellular matrix remodeling, epithelial-mesenchymal transition, and angiogenic signaling. Extensive clinical evidence is integrated to establish systemic and local elemental imbalances as risk biomarkers across diverse cancer types. Therapeutic strategies are categorized into traditional nutritional and pharmacological interventions, element-metabolism-based synergistic sensitization with chemotherapy, radiotherapy, and immunotherapy, and interdisciplinary engineering approaches including element-responsive nanoplatforms and synthetic biology-engineered immune cells. Throughout, we emphasize that the majority of therapeutic evidence derives from preclinical models, underscoring that rigorous foundational research must precede clinical translation. We conclude by outlining knowledge gaps and priorities for future investigation, advocating a systems biology framework that acknowledges current limitations while guiding hypothesis-driven exploration.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149270880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in improving cancer immunotherapy with nanotechnology: from smart nanoparticles to synergistic combination strategies.","authors":"Untack Cho, Jingjing Pu, Amit Sharma, Junhyuk Song, Ji Hyeon You, Yona Kim, Pyung Won Im, Hyung Woo Park, Hyo Eun Moon, Ho Sung Myeong, Hye Ran Park, Jian Hou, Ingo G H Schmidt-Wolf, Sun Ha Paek","doi":"10.1186/s12943-026-02736-0","DOIUrl":"10.1186/s12943-026-02736-0","url":null,"abstract":"<p><p>Cancer immunotherapy has substantially advanced cancer treatment, achieving durable responses in select malignancies. However, its widespread application is limited by significant challenges: low efficacy in many solid tumors, severe side effects, and immune evasion facilitated by the tumor microenvironment (TME). Nanotechnology offers a promising approach to address these obstacles. By employing nanoparticles (NPs), we can precisely deliver therapeutics to tumor sites, ensure controlled release to minimize side effects, and amplify the immune response, thereby substantially boosting the effectiveness of immunotherapy. This review comprehensively highlights the latest advancements in using nanotechnology to enhance cancer immunotherapy. This paper details various applications of nanotech in this field. It discusses smart nanoparticles that respond to TME signals to release drugs (e.g., checkpoint inhibitors) directly at the tumor, reducing systemic side effects and activating T-cells. We also explore how nanovaccines, which co-deliver tumor markers and immune boosters, can induce antigen-specific immune responses. Furthermore, mRNA-loaded nanoparticles can directly modify CAR T-cells inside the body, simplifying treatment and increasing efficacy. Strategies like using PLGA NPs to deliver immune enhancers such as IL-2 are also presented, which activate immune cells while minimizing systemic issues. The review also explains how nanoparticles can re-engineer the immunosuppressive TME to create an environment more conducive to immune action. We also emphasize that nanotechnology-enhanced adoptive therapies, particularly cytokine-induced killer (CIK) cell immunotherapy, hold great potential to improve tumor targeting, treatment persistence durability, and overall anticancer efficacy. Collectively, we highlight synergistic effects achieved by combining nanoparticles with other treatments like chemotherapy, radiation, photothermal/photodynamic therapy, and more, which can turn hard-to-treat tumors into susceptible targets. The integration of nanotechnology and immunotherapy holds the potential to meaningfully advance future cancer therapy.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13419314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}