Sex differences in cancer immunotherapy: clues from first-line monotherapy for advanced NSCLC; personalized treatment remains to be validated
Relative benefit by sex has not been established as a treatment rule
In first-line immune checkpoint inhibitor monotherapy for advanced non-small cell lung cancer (NSCLC), the relative benefit compared with chemotherapy has tended to be greater in men than in women. This finding comes from a review synthesizing clinical trials and mechanistic studies. However, it does not establish a treatment rule that monotherapy is best for men and chemoimmunotherapy is best for women.
Published in Immunological Reviews in March 2026, this paper is a review of existing research, not a clinical trial that recruited a new patient cohort. The researchers examined sex differences in treatment response and their relationships with the tumor microenvironment, sex hormones, sex chromosomes, and lifestyle, focusing on NSCLC.
Different signals observed with monotherapy and combination therapy
KEYNOTE-024, cited in the review, compared first-line pembrolizumab monotherapy with platinum-based chemotherapy in patients with stage IV NSCLC and PD-L1 expression of at least 50%. The participants included 187 men and 118 women. In the 2019 analysis, the hazard ratio for death was 0.54 (95% confidence interval, 0.36–0.79) in men and 0.95 (0.56–1.62) in women. The relative benefit compared with chemotherapy within each sex was greater in men.
By contrast, in the final analysis of KEYNOTE-189, which evaluated first-line treatment for metastatic nonsquamous NSCLC, the hazard ratios for death with pembrolizumab plus chemotherapy versus chemotherapy alone were 0.74 (95% confidence interval, 0.56–0.96) in men and 0.41 (0.30–0.56) in women. However, combination therapy studies did not all show the same pattern. Some trials found small sex differences, while others showed numerically greater benefit in men; results were also mixed for second-line or later treatment and perioperative treatment.
These figures do not directly compare survival between men and women or establish which is better, immunotherapy alone or combination therapy. Outcomes in the chemotherapy control group also affect the hazard ratios. Statistical significance in only one sex does not prove a difference in treatment effect between sexes. When fewer women participate, estimates are more uncertain, and confidence intervals for men and women overlapped in several trials. This is why absolute outcomes, such as actual survival time, should be considered alongside relative benefit.
Links between hormones and immune cells also varied by context
Separate experimental studies included in the review offer possible biological explanations. In some mouse tumor models, androgen receptor signaling was involved in dysfunction and exhaustion of CD8 T cells, which attack cancer cells. Exhaustion refers to a state in which T-cell function declines under persistent stimulation. Blocking this signaling slowed tumor growth, but the additional effect of immune checkpoint inhibitors varied with experimental conditions. In some studies, T-cell states observed in human tumor samples and in mice also differed.
Estrogen’s effects likewise varied by cancer type and receptor type. Factors related to the X and Y chromosomes were also discussed, but the influence of accompanying variables such as smoking history, tumor mutations, age, and hormonal status needs to be disentangled. The evidence does not yet justify explaining sex differences through a single hormone or interpreting preclinical findings as clinical efficacy of combination treatment involving hormone suppression.
Direct comparative trials and adequate analyses by sex are needed
A key evidence gap is the lack of evidence directly comparing monotherapy with chemoimmunotherapy under the same conditions and testing whether treatment effects differ by sex. According to a 2025 European Society for Medical Oncology presentation described in the review, the PAULIEN randomized trial in patients with NSCLC and PD-L1 expression of at least 50% was terminated after its first interim analysis found no difference in response at 6 weeks of treatment. The analysis then included 72 participants, too few for a subgroup analysis by sex. This does not mean that long-term survival or treatment effects by sex are the same.
The review authors said they had secured funding for the IFEM randomized phase 3 trial, which will directly compare the two strategies in more than 400 women with NSCLC. This is a plan for validation, not a treatment result. The review concluded that sex is not currently a routine criterion for guiding cancer treatment selection and that studies need adequate numbers of participants of each sex as well as clinical and molecular data.
For detailed evidence, see the full review and PubMed citation and abstract.
Accumulating evidence suggests that the immune system shows subtle but relevant differences between men and women. These differences may have an impact on cancer development and TME composition as well as responses to and adverse events elicited by immunotherapies. Several, albeit not all, clinical trials indicate a greater benefit from mono-immunotherapies over chemotherapies for male patients than for female patients, especially in non-small cell lung cancer and melanoma. Vice versa, female patients might benefit more from chemo-immunotherapies. In human as well as animal models, sex differences in cancer microenvironment composition were described, with partially divergent results. Sex-specific factors such as the levels of hormones, in particular testosterone and estrogen, or X- or Y-chromosome associated genes are likely to drive the observed differences, but are often confounded by external influences such as smoking behavior, diet, or UV exposure. Therefore, large clinical and mechanistic knowledge gaps remain regarding the influence of sex on cancer immunotherapies and strategies to optimize response in either sex. More clinical as well as experimental research in this field is required to close these knowledge gaps, and clinical trials should include large enough groups of male and/or female patients to allow robust sex-specific analyses.
This review brings together sex differences that may be missed when looking only at average effects in existing clinical trials, along with the research conditions needed to validate them. Researchers need to go beyond presenting hazard ratios for men and women side by side: they should test differences in treatment effects between sexes and assess control-group outcomes, absolute survival time, and toxicity together. Linking smoking history, tumor genetic features, and hormonal status with clinical data and sample analyses may help distinguish the effect of sex itself from accompanying factors. The hormone–immune cell link suggested by separate animal studies offers hypotheses for future research, but it is not clinical evidence to support changing patient treatment or adding hormone suppression.