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Immune checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 can yield durable responses, yet benefit is confined to subsets of patients due to immune evasion, tumor heterogeneity, and an immunosuppressive tumor microenvironment (TME). This review surveys emerging next-generation immune checkpoints, detailing co-inhibitory and co-stimulatory pathways, their mechanisms, translational rationale, and early clinical evidence, and integrates complementary TME remodeling strategies including immunometabolism, innate sensing, cytokine signaling, micronutrient regulation, and gut microbiota.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/next-generation-immune-checkpoints-and-tumor-microenvironment-modulation-in-cancer-immunotherapy/355647/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/next-generation-immune-checkpoints-and-tumor-microenvironment-modulation-in-cancer-immunotherapy/355647.png","ImageObject",300,407,{"name":92,"@type":93},"Melati","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why do immune checkpoint inhibitors show limited benefit across all patients?","Question",{"text":113,"@type":114},"Benefits are heterogeneous because immune evasion, tumor heterogeneity, and immunosuppressive features of the tumor microenvironment limit long-term effectiveness.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which next-generation immune checkpoint pathways are covered in the review?",{"text":118,"@type":114},"The review addresses expanding co-inhibitory pathways such as LAG-3, TIM-3, TIGIT, VISTA, and IGSF8, and co-stimulatory pathways such as ICOS, OX40, GITR, 4-1BB, CD40, and CD27.",{"name":120,"@type":111,"acceptedAnswer":121},"What complementary strategies are discussed beyond immune checkpoint modulation?",{"text":122,"@type":114},"Strategies include remodeling the TME through immunometabolic targets (IDO1, CD73), innate immune sensing via toll-like receptors, cytokine signaling (IL-2), micronutrient regulation (vitamin D), and the gut microbiota.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},355647,1790144839,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":31},962085570644,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Journal of Immunology Research  \nREVIEW ARTICLE OPEN ACCESS  \nNext-Generation Immune Checkpoints and Tumor  \nMicroenvironment Modulation in Cancer Immunotherapy  \nJhommara Bautista1  | Carolina E. Echeverría2 | Iván Maldonado-Noboa3 | Joseth Adatty-Molina4 | Salomé Suárez Urresta1 | Emily C. Coral-Riofrio1 | Salomé Araujo-Abad5 | Nikolaos C. Kyriakidis6 | Andrés López-Cortés1   \n1Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador | 2Department of Medicine, New York University Grossman School of Medicine, New York, USA | 3Jefe de servicio de oncología, Hospital Metropolitano de Quito, Quito, Ecuador | 4Hospital General Universitario Dr. Balmis, Alicante, Spain | 5Cancer Research Group, Faculty of Engineering and Applied Sciences, Universidad de Las Américas, Quito, Ecuador | 6Center for  \nHematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden Correspondence: Andrés López-Cortés ([aalc84@gmail.com](aalc84@gmail.com))  \nReceived: 13 August 2025 | Revised: 13 December 2025 | Accepted: 17 January 2026  \nAcademic Editor: Poorani Gurumallesh Prabu  \nABSTRACT  \nImmunotherapy has reshaped the oncology landscape by enabling the immune system to recognize and eliminate malignant cells. Although immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed death-ligand 1 (PD-L1) have achieved durable responses in several cancers, their therapeutic benefit remains limited to a subset of patients, largely due to immune evasion, tumor heterogeneity, and immunosuppressive features of the tumor microenvironment (TME) . This review comprehensively examines the expanding landscape of nextgeneration immune checkpoints, encompassing both co-inhibitory (lymphocyte activation gene-3 [LAG-3], T cell immunoglobulin and mucin-domain containing-3 [TIM-3], TIGIT, VISTA, and IGSF8) and co-stimulatory (ICOS, OX40, GITR, 4-1BB, CD40, and CD27) pathways that collectively regulate the balance between immune activation and tolerance. We discuss their molecular mechanisms, translational rationale, and emerging clinical evidence, highlighting their potential to reinvigorate antitumor immunity, particularly in ICI-refractory settings. Beyond checkpoint modulation, we explore complementary strategies aimed at remodeling the TME and enhancing immune responsiveness, including targeting immunometabolic pathways (IDO1 and CD73), innate immune sensing (toll-like receptors [TLRs]), cytokine signaling (IL-2), micronutrient immunoregulators (vitamin D), and the gut microbiota. The integration of these approaches into rational combination regimens, guided by predictive features such as T cell infiltration, tumor mutational burden (TMB), and microbiome composition, holds promise for extending the clinical impact of immunotherapy across malignancies. We further advocate for a precision immuno-oncology framework that leverages multiomic profiling, systems biology, and artificial intelligence (AI) to optimize therapeutic selection and mitigate immunerelated toxicities. Emerging advances in nanomedicine, synthetic biology, and chronotherapy offer additional opportunities to enhance therapeutic specificity and durability, collectively charting a path from mechanistic insight to clinical translation toward realizing the full curative potential of cancer immunotherapy.  \nTrial Registration: [ClinicalTrials.gov](ClinicalTrials.gov) identifier: LAG-3 (NCT03470922, NCT04082364, NCT05064059, NCT05352672, NCT02614833, NCT03625323, NCT01968109), TIM-3 (NCT03307785, NCT03680508, NCT02608268, NCT02817633), TIGIT (NCT03563716), VISTA (NCT02671955, NCT02812875), IGSF8 (NCT05669430), CD73 (NCT02503774), B7-H3 (NCT02475213, NCT01391143, NCT02628535, NCT03406949, NCT00089245, NCT01099644, NCT01502917), OX40 (NCT01862900, NCT02315066, NCT02410512, NCT02221960, NCT02528357, NCT02923349, NCT02705482), CD27 (NCT02335918, N","cbCaiadb21aj59f3","https://ap.wps.com/l/cbCaiadb21aj59f3","pdf",1454037,"English","# Abstract\n# Introduction\n## Immune checkpoint inhibitors and clinical outcomes\n## Resistance mechanisms and the role of the tumor microenvironment\n# Emerging next-generation immune checkpoints\n## Co-inhibitory pathways\n## Co-stimulatory pathways\n# Complementary strategies beyond checkpoint modulation\n## Immunometabolic and innate sensing targets\n## Cytokine signaling, micronutrients, and gut microbiota\n# Predictive biomarkers and combination regimens\n## T cell infiltration, TMB, and microbiome composition\n# Precision immuno-oncology and future directions\n## Multiomics, systems biology, and AI optimization\n## Nanomedicine, synthetic biology, and chronotherapy","[{\"question\":\"Why do immune checkpoint inhibitors show limited benefit across all patients?\",\"answer\":\"Benefits are heterogeneous because immune evasion, tumor heterogeneity, and immunosuppressive features of the tumor microenvironment limit long-term effectiveness.\"},{\"question\":\"Which next-generation immune checkpoint pathways are covered in the review?\",\"answer\":\"The review addresses expanding co-inhibitory pathways such as LAG-3, TIM-3, TIGIT, VISTA, and IGSF8, and co-stimulatory pathways such as ICOS, OX40, GITR, 4-1BB, CD40, and CD27.\"},{\"question\":\"What complementary strategies are discussed beyond immune checkpoint modulation?\",\"answer\":\"Strategies include remodeling the TME through immunometabolic targets (IDO1, CD73), innate immune sensing via toll-like receptors, cytokine signaling (IL-2), micronutrient regulation (vitamin D), and the gut microbiota.\"}]","Next-Generation Immune Checkpoints and Tumor Microenvironment Modulation in Cancer Immunotherapy | PDF",1790120290]