Dlamini, ZodwaAlaouna, MohammedMarutha, TebogoMkhize-Kwitshana, ZilungileMbodi, LangananiChauke-Malinga, NkhensaniLuvhengo, Thifhelimbil E.Marima, RahabaHull, RodneySkepu, AmandaNtwasa, MondeDuarte, RaquelDamane, Botle PreciousMosoane, BennyMbatha, Sikhumbuzo Z.Phakathi, BoitumeloKhaba, MoshawaChokwe, Ramakwana ChristinahEdge, JennyMbita, ZukileKhanyile, RichardMolefi, Thulo2025-09-042025-09-042025-08Dlamini, Z.; Alaouna, M.; Marutha, T.; Mkhize-Kwitshana, Z.; Mbodi, L.; Chauke-Malinga, N.; Luvhengo, T.E.; Marima, R.; Hull, R.; Skepu, A.; et al. The Exposome Perspective: Environmental and Infectious Agents as Drivers of Cancer Disparities in Low- and Middle- Income Countries. Cancers 2025, 17, 2537. https://doi.org/10.3390/cancers17152537.2072-6694 (online)10.3390/cancers17152537http://hdl.handle.net/2263/104199DATA AVAILABILITY STATEMENT : Data sharing is not applicable to this review, as no new datasets were generated or analyzed.Cancer disparities in low- and middle-income countries (LMICs) arise from multifaceted interactions between environmental exposures, infectious agents, and systemic inequities, such as limited access to care. The exposome, a framework encompassing the totality of non-genetic exposures throughout life, offers a powerful lens for understanding these disparities. In LMICs, populations are disproportionately affected by air and water pollution, occupational hazards, and oncogenic infections, including human papillomavirus (HPV), hepatitis B virus (HBV), Helicobacter pylori (H. pylori), human immunodeficiency virus (HIV), and neglected tropical diseases, such as schistosomiasis. These infectious agents contribute to increased cancer susceptibility and poor outcomes, particularly in immunocompromised individuals. Moreover, climate change, food insecurity, and barriers to healthcare access exacerbate these risks. This review adopts a population-level exposome approach to explore how environmental and infectious exposures intersect with genetic, epigenetic, and immune mechanisms to influence cancer incidence and progression in LMICs. We highlight the critical pathways linking chronic exposure and inflammation to tumor development and evaluate strategies such as HPV and HBV vaccination, antiretroviral therapy, and environmental regulation. Special attention is given to tools such as exposome-wide association studies (ExWASs), which offer promise for exposure surveillance, early detection, and public health policy. By integrating exposomic insights into national health systems, especially in regions such as sub-Saharan Africa (SSA) and South Asia, LMICs can advance equitable cancer prevention and control strategies. A holistic, exposome-informed strategy is essential for reducing global cancer disparities and improving outcomes in vulnerable populations.SIMPLE SUMMARY People in low- and middle-income countries face a higher risk of developing cancer owing to exposure to harmful environmental and infectious factors. These include polluted air and water, chemicals used in farming and industry, and infections such as HIV, hepatitis, and human papillomavirus. These exposures often occur together and can worsen their effects, especially when healthcare is difficult to access. This article looks at how a person’s total exposure to these harmful influences throughout their life, what scientists call the “exposome”, can help explain why cancer is more common and lethal in poorer countries. This study also explored how these risks affect individuals differently, based on their genes, diets, and living conditions. By understanding the full picture of exposure, this study shows how public health strategies can be improved. These include vaccination, early screening, safe work and home environments, and robust health systems. These findings are especially important for regions such as sub-Saharan Africa and South Asia, where cancer rates are increasing. This research helps point the way toward fairer and more effective methods for preventing and treating cancer worldwide.en© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Low- and middle-income countries (LMICs)Human papillomavirus (HPV)Hepatitis B virus (HBV)Helicobacter pylori (H. pylori)Human immunodeficiency virus (HIV)Neglected tropical diseasesEpigeneticsGlobal health disparitiesOncogenic infectionsCancer inequitiesExposomeEnvironmental exposuresHIV-related cancersArticle