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These immunomodulatory secretomes can enhance antigen presentation and T cell–mediated anticancer immunity, but in certain contexts they also recruit immunosuppressive cells that support tumor progression. How cancer cell death reshapes the tumor microenvironment to produce antitumor versus protumor outcomes remains largely unclear, limiting effective mechanistic assessment. This perspective highlights understudied determinants and future study directions accounting for tumor genetics, epigenetics, and oncogenic factors.",{"@graph":69,"@context":122},[70,84,105],{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/determinants-for-antitumor-and-protumor-effects-of-programmed-cell-death/329958/",{"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/determinants-for-antitumor-and-protumor-effects-of-programmed-cell-death/329958.png","ImageObject",300,407,{"name":92,"@type":93},"Jiven","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How can programmed cell death lead to antitumor immune responses?","Question",{"text":112,"@type":113},"Immunogenic cell death releases danger signals, cytokines, and chemokines that stimulate antigen presentation and T cell–mediated anticancer immunity. Dying cancer cells activate innate immune cells and support cytotoxic T-cell responses.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"In what situations can cell death promote tumor progression?",{"text":117,"@type":113},"Some cell death–associated secretomes recruit immunosuppressive cells, such as MDSCs or IgAþPD-L1þIL10-producing plasmocytes. This immunosuppressive recruitment can enhance tumor progression in certain cancers.",{"name":119,"@type":110,"acceptedAnswer":120},"Why are the antitumor versus protumor effects of cell death difficult to study?",{"text":121,"@type":113},"Cell death is often subverted by tumors to evade immunosurveillance, including therapy-induced changes. Additionally, chemotherapies can simultaneously activate multiple premortem stress and cell death pathways in both neoplastic and immune cells.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},329958,1790198027,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":24,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":52,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144,"preview_page_count":4},1099513958607,"https://ap-avatar.wpscdn.com/avatar/100002390cf8733938c?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778829742770036399","Determinants for Antitumor and Protumor Effects of Programmed Cell Death  \nSamuel T. Workenhe, Jordon M. Inkol, Michael J. Westerveld, Shayla G. Verburg, Sarah M. Worfolk, Scott R. Walsh, and Kaslyn L. F. Kallio  \nABSTRACT  \n◥  \nCytotoxic anticancer therapies activate programmed cell death in the context of underlying stress and inflammatory signaling to elicit the emission of danger signals, cytokines, and chemokines. In a concerted manner, these immunomodulatory secretomes stimulate antigen presentation and T cell–mediated anticancer immune responses. In some instances, cell death–associated secretomes attract immunosuppressive cells to promote tumor progression. As it stands, cancer cell death–induced changes in the tumor microenvironment that contribute to antitumor or protumor effects remain largely unknown. This is complicated to examine because  \ncell death is often subverted by tumors to circumvent natural, and therapy-induced, immunosurveillance. Here, we provide insights into important but understudied aspects of assessing the contribution of cell death to tumor elimination or cancer progression, including the role of tumor-associated genetics, epigenetics, and oncogenic factors in subverting immunogenic cell death. This perspective will also provide insights on how future studies may address the complex antitumor and protumor immunologic effects of cell death, while accounting for variations in tumor genetics and underlying microenvironment.  \nThe Contribution of Programmed Cell Death to Immunity  \nThe maintenance of organismal development and tissue homeostasis requires a balance between the production of new cells and clearance of stressed and dying cells. Programmed cell death is a highly regulated process used to not only clear unneeded cells, but also to communicate homeostatic disturbances, such as danger and tissue injury, to the immune system. Hence, cell death can elicit immune responses against malignancies (1, 2) and pathogens (3) . The interaction of dying cancer cells with the immune system has been intensively studied across a variety of model systems, revealing that programmed cell death can elicit an antitumor (4–9) or protumor immune response (10–12) .  \nStudies investigating the role of cell death in the initiation of anticancer immunity started with the exploration of how apoptotic cells communicate with dendritic cells (DC; refs. 13–19) . Subsequent studies using cytotoxic anticancer agents, such as cytotoxic chemotherapies (20), radiation(21), oncolytic viruses(22), photodynamic therapy (23), extracorporeal photochemotherapy (24, 25), facilitated the rapid identification of mechanistic details associated with the immunogenicity of cell death and its contribution to anticancer immunity(20,26–29). Two decades later, we have gained a remarkable understanding of the types of cell stress and programmed cell death that contribute to the emission of molecules (Fig. 1) and their role in shaping anticancer immunity (Fig. 2) .  \nDepartment of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.  \nCorresponding Author: Samuel T. Workenhe, University of Guelph, PAHL Bldg 89, Rm 4828, Guelph, Ontario N1G 2W1, Canada. E-mail: [sworkenh@uoguelph.ca](sworkenh@uoguelph.ca)[ ](sworkenh@uoguelph.ca)[Cancer Immunol Res 2024](Cancer Immunol Res 2024);[12:7](12:7)–[16](16)  \n[doi:](doi: 10.1158/2326-6066.CIR-23-0321)[ 10.1158/2326-6066.CIR-23-0321](doi: 10.1158/2326-6066.CIR-23-0321)  \nThis open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4 . 0 International (CC BY-NC-ND 4 . 0) license.  \n􀀁2023The Authors;Published by the American Association for Cancer Research  \nDanger signals, cytokines, and chemokines emitted during immunogenic cell death (ICD) promote the activation, maturation, and trafficking of innate immune cells. Specifically, surface-expressed “eat me”signals, such as calreticulin, attract antigen-presenting cells (mainly D","cbCaikgvEAqW7j6A","https://ap.wps.com/l/cbCaikgvEAqW7j6A","pdf",3156244,"English","# Abstract\n## The Contribution of Programmed Cell Death to Immunity\n## What Types of Programmed Cell Death Are Immunostimulatory?","[{\"question\":\"How can programmed cell death lead to antitumor immune responses?\",\"answer\":\"Immunogenic cell death releases danger signals, cytokines, and chemokines that stimulate antigen presentation and T cell–mediated anticancer immunity. Dying cancer cells activate innate immune cells and support cytotoxic T-cell responses.\"},{\"question\":\"In what situations can cell death promote tumor progression?\",\"answer\":\"Some cell death–associated secretomes recruit immunosuppressive cells, such as MDSCs or IgAþPD-L1þIL10-producing plasmocytes. This immunosuppressive recruitment can enhance tumor progression in certain cancers.\"},{\"question\":\"Why are the antitumor versus protumor effects of cell death difficult to study?\",\"answer\":\"Cell death is often subverted by tumors to evade immunosurveillance, including therapy-induced changes. Additionally, chemotherapies can simultaneously activate multiple premortem stress and cell death pathways in both neoplastic and immune cells.\"}]","Determinants for Antitumor and Protumor Effects of Programmed Cell Death | PDF",1789986312,25]