Age and sex are dual drivers that profoundly remodel the anti-tumor immune microenvironment through distinct mechanisms, including immunosenescence, inflammaging, sex chromosome genomics, sex hormone networks, metabolic reprogramming, and gut microbiome differences, with critical implications for disparities in immune checkpoint inhibitor efficacy and toxicity.
Key Findings
Background
Immunosenescence drives progressive functional decline of T and B lymphocytes as well as innate immune subsets, contributing to altered anti-tumor immune responses with aging.
The review systematically outlines the age-related functional decline affecting both adaptive immune cells (T/B lymphocytes) and innate immune subsets.
Immunosenescence is identified as a key mechanism through which aging shapes tumor susceptibility and disease progression.
These immune changes are described as 'progressive,' suggesting a cumulative deterioration over time rather than a discrete threshold effect.
Background
Inflammaging and its associated senescence-associated secretory phenotype (SASP) orchestrate the formation of an immunosuppressive tumor microenvironment.
Inflammaging refers to chronic low-grade inflammation associated with aging.
The SASP is identified as a key mediator through which senescent cells reshape the tumor microenvironment toward immunosuppression.
This mechanism is described as 'emphatically revealed,' indicating it is a central finding of the age-related dimension of the review.
The immunosuppressive tumor microenvironment created by inflammaging/SASP is presented as a driver of immune evasion in older patients.
Background
Escape from X-chromosome inactivation and loss of the Y chromosome represent sex chromosome genomic mechanisms driving immune disparities between males and females in the tumor microenvironment.
X-chromosome inactivation escape allows certain X-linked immune-regulatory genes to be expressed at higher levels in females.
Loss of the Y chromosome (LOY) is identified as a sex-specific genomic event relevant to male anti-tumor immunity.
These are presented as part of four core sex-based mechanisms shaping the anti-tumor immune response.
Sex chromosome genomics is distinguished from hormonal mechanisms as an independent driver of immune sex differences.
Background
Sex hormone networks constitute a core mechanism driving disparities in innate and adaptive immunity between males and females.
Sex hormones are identified as one of four core mechanisms explaining male-female immune differences in the tumor context.
The review elucidates 'the molecular basis driving the disparities in innate and adaptive immunity between males and females' through hormone-mediated pathways.
Both innate and adaptive immune compartments are affected by sex hormone signaling differences.
Background
Microenvironmental metabolic reprogramming and host gut microbiome composition are identified as sex-specific mechanisms shaping anti-tumor immune responses.
Metabolic reprogramming within the tumor microenvironment is described as differing between sexes.
The gut microbiome is identified as a host-level variable that differs between males and females and contributes to immune response disparities.
These represent the third and fourth of four core sex-based mechanisms outlined in the review.
Both mechanisms are presented as contributing to the 'molecular basis' of sex-based immune differences in oncology.
Background
Age and sex contribute to inter-individual heterogeneity in immune checkpoint inhibitor (ICI) efficacy and toxicity.
The review identifies age- and sex-driven immune regulatory networks as explanatory factors for 'disparities in efficacy and toxicity observed in patients undergoing immune checkpoint inhibitors.'
The analysis covers both response rates (efficacy) and adverse event profiles (toxicity) as outcomes influenced by these biological variables.
This finding is framed as emerging from 'accumulating fundamental and clinical evidence.'
Conclusions
The authors propose that deciphering age- and sex-driven immune regulatory networks provides the theoretical foundation for developing 'age-tailored' and 'sex-specific' personalized immuno-oncology strategies.
The review explicitly calls for future development of strategies described as 'age-tailored' and 'sex-specific' in personalized immuno-oncology.
These strategies are framed as requiring 'crucial theoretical foundations and translational insights' that the review aims to provide.
The personalization approach is positioned as a response to the 'significant inter-individual heterogeneity in clinical outcomes' that persists despite immunotherapy breakthroughs.
What This Means
This research suggests that two fundamental biological characteristics — a person's age and biological sex — play major roles in determining how well the immune system can fight cancer and respond to immunotherapy treatments like immune checkpoint inhibitors. As people age, their immune systems undergo a process called immunosenescence, where immune cells become less effective at recognizing and attacking tumors. Alongside this, chronic low-grade inflammation associated with aging (called 'inflammaging') and a related process called the senescence-associated secretory phenotype (SASP) can actually help tumors evade immune detection by creating a suppressive environment around the tumor. This helps explain why older cancer patients often experience different outcomes from immunotherapy compared to younger patients.
On the sex side, this research suggests that biological differences between males and females — including how X and Y chromosomes function, how sex hormones like estrogen and testosterone influence immune cells, differences in metabolism within tumors, and even differences in gut bacteria — all contribute to meaningful differences in immune responses against cancer. For example, females have more active immune responses in some respects due to having two X chromosomes (some immune genes on the X chromosome escape normal silencing), while males face a unique vulnerability through age-related loss of the Y chromosome in immune cells.
This research matters because it helps explain why cancer immunotherapy works better for some people than others, and why side effects also vary. Currently, most treatment protocols do not systematically account for a patient's age or sex. This review argues that building 'age-tailored' and 'sex-specific' immunotherapy strategies could improve both the effectiveness of cancer treatment and the safety profiles for individual patients, pointing toward a more personalized approach to cancer care.
Wang Y, Wang T, Xi Y, Wang Y, Bai Y, Zhang T. (2026). Age and sex: dual drivers remodeling the anti-tumor immune microenvironment and shaping personalized immuno-oncology.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1918543