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Journal of Translational Medicine (2025) 23:115  \n[https://doi.org/10.1186/s12967-025-06151-9](https://doi.org/10.1186/s12967-025-06151-9)  \nJournal of Translational Medicine  \n REVIEW Open Access  \nDecoding the mechanisms behind second   primary cancers  \nMeiyuan Zeng1†, Anqi Lin1†, Aimin Jiang2†, Zhengang Qiu3†, Hongman Zhang1, Shifu Chen4,5, Mingyan Xu4, Zaoqu Liu6, Quan Cheng7,8*, Jian Zhang1* and Peng Luo 1*  \nAbstract  \nSecond Primary Cancers (SPCs) are defined as cancers that develop either simultaneously or metachronouslyin the same individual who has been diagnosed with and survived one primary cancer. SPCs exhibit a high incidence rate and represent the primary cause of mortality among survivors of first primary cancers. There is growing concern about the dangers of SPCs. This review summarizes recent studies on the mechanisms of SPCs, including the roles of genomic changes after first primary cancer (FPC) treatments, stromal cell phenotypic and metabolic changes, hormone levels and receptor expression, immunosuppression, aberrant gene methylation, EGFR signaling, and cellfree DNA in SPC development. This comprehensive analysis contributes to elucidating current research trends in SPC mechanisms and enhances our understanding of the underlying pathophysiology. Furthermore, potential applications of intratumoral microbes, single-cell multi-omics, and metabolomics in investigating SPC mechanisms are also discussed, providing new ideas for follow-up studies.  \nKeywords Second Primary Cancers, Mechanisms, Tumorigenesis, Immune  \n†Meiyuan Zeng, Anqi Lin, Aimin Jiang and Zhengang Qiu have contributed equally to this work and share first authorship.  \n*Correspondence:  \nQuan Cheng [chengquan@csu.edu.cn](chengquan@csu.edu.cn)[ ](chengquan@csu.edu.cn)Jian Zhang [zhangjian@i.smu.edu.cn](zhangjian@i.smu.edu.cn)[ ](zhangjian@i.smu.edu.cn)Peng Luo [luopeng@smu.edu.cn](luopeng@smu.edu.cn)  \n1 Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou 510282, Guangdong, China  \n2 Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China  \n3 Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China  \n4 HaploX Biotechnology, Shenzhen, China  \n5 Faculty of Data Science, City University of Macau, Macau, China  \n6 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China  \n7 Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China  \n8 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China  \nIntroduction  \nSecond Primary Cancers (SPCs) are defined as cancers that develop either simultaneously or metachronouslyin the same individual who has been diagnosed with and survived one primary cancer [1]. The significance of SPCs stems from their high incidence and substantial impact on first primary cancer (FPC) survivors. The incidence of SPCs varies widely, ranging from 2.4% to 19.0%[2–4]. A previous meta-analysis, encompassing a pooled cohort of 9,617,643 cancer patients, of whom 677,430 developed SPCs, examined the absolute numbers of patients with various types of FPCs who subsequently developed SPCs. The study revealed that among 1,825,198 breast cancer patients, 1,181,621 prostate cancer patients, and 711,504 skin cancer patients, 117,178, 111,150, and 76,517 respectively developed SPCs, ranking these three cancer types as the most prevalent in terms of SPC occurrence. Upon analyzing the incidence of SPCs among patients with various FPCs, the study revealed that patients with primary ureteral cancer exhibited the highest SPC incidence  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, w","cbCaiekk03CTHTrs","https://ap.wps.com/l/cbCaiekk03CTHTrs","pdf",1663802,18,"English","# Abstract\n# Introduction\n## Definition and clinical significance\n## Incidence patterns and meta-analysis findings\n## Risk comparison with general population\n## Shared cancer pathways and ongoing debate\n# Mechanistic overview of SPC tumorigenesis\n## Genomic, stromal, hormonal, and immune factors\n## Epigenetics, signaling, and cell-free DNA","[{\"question\":\"How are Second Primary Cancers (SPCs) defined?\",\"answer\":\"SPCs are cancers that arise either simultaneously or metachronously in the same individual after one primary cancer diagnosis and survival.\"},{\"question\":\"Why are SPCs a major concern for first primary cancer (FPC) survivors?\",\"answer\":\"SPCs have a high incidence and substantially increase mortality risk among FPC survivors, making them a leading cause of death.\"},{\"question\":\"Which biological mechanisms does the review highlight for SPC development?\",\"answer\":\"The review covers genomic changes after FPC treatment, stromal phenotypic and metabolic changes, hormone and receptor shifts, immunosuppression, aberrant gene methylation, EGFR signaling, and cell-free DNA. It also discusses potential roles of intratumoral microbes and single-cell multi-omics/metabolomics.\"}]","Decoding the mechanisms behind second primary cancers | PDF",1790157040,45]