In a groundbreaking study shedding light on age-related immune decline, researchers have demonstrated that transient reconstitution of specific trophic factors in the liver can markedly enhance antitumour immune responses in aged hosts. This innovative approach, leveraging mRNA-lipid nanoparticle (LNP) delivery to restore a youthful hepatic environment, holds promise for overcoming the long-standing issue of diminished efficacy in cancer immunotherapy among elderly populations.
Aged organisms characteristically suffer from impaired immunity, including reduced responsiveness to immune checkpoint inhibition (ICI) therapy, which is pivotal in modern cancer treatment. The study explored the potential of hepatic delivery of a defined set of trophic factors—referred to as DFI—to rejuvenate the immune system’s capacity to combat tumours in aged mice. Employing models of both melanoma (B16-OVA) and colon carcinoma (MC38-OVA), the researchers observed that older mice typically exhibited rapid tumour growth and poor survival compared to younger adult controls when subjected to PDL1 checkpoint blockade therapy.
Intriguingly, aged mice pre-conditioned with the transient hepatic expression of DFI for 28 days, followed by a brief washout period to mitigate direct anti-tumour effects, showed substantially improved tumour control. Spontaneous tumour rejection rates increased, and survival outcomes were significantly prolonged. In the aggressive B16-OVA melanoma model, 40% of aged mice treated with DFI achieved complete tumour rejection, contrasting starkly with the 100% mortality rate in control groups despite anti-PDL1 therapy—a compelling demonstration of the rejuvenative power of hepatic DFI expression.
Further, the combinatory regimen of adjuvant DFI administration initiated at the onset of immunotherapy greatly enhanced therapeutic efficacy in aged mice bearing established tumours. This combination therapy not only delayed tumour progression but also notably improved survival compared to PDL1 blockade alone. These observations spotlight the potential for hepatic trophic factor reconstitution to sensitize otherwise refractory tumours to checkpoint inhibitors in aged hosts.
Mechanistic insight was gleaned by characterizing tumour-infiltrating lymphocytes (TILs) from treated aged mice prior to significant tumour size divergences. Although total TIL numbers remained unchanged, DFI treatment shifted the immune cell landscape within the tumour microenvironment, significantly increasing the proportion of CD8+ T cells while reducing the CD4:CD8 ratio. Notably, antigen-specific CD8+ T cells, identified via SIINFEKL-loaded MHC class I tetramers, were enriched intratumourally, indicating enhanced tumour-targeted immune surveillance.
Systemic analysis revealed expansion of naive CD8+ T cells, suggesting that the rejuvenation effects of hepatic DFI extended beyond the tumour microenvironment, replenishing peripheral immune pools critical for effective antitumour responses. This systemic effect underscores the liver’s broader immunomodulatory role when appropriately stimulated by transient trophic factor expression.
At the single-cell transcriptomic level, comprehensive scRNA–V(D)J profiling combined with CITE-seq unveiled heterogeneity within the TIL compartment and distinguished tumour-specific from bystander T cell clonotypes. DFI treatment yielded diminished expression of exhaustion-associated genes such as Havcr2, Gzmk, Lag3, Pdcd1, and Tigit among CD8+ TILs. This transcriptional shift suggests alleviation of T cell dysfunction, restoring their functional potential and sustaining effective immune activity within the tumour milieu.
Moreover, despite reduced exhaustion markers, an increase in CD39 (Entpd1) expression was detected, a hallmark consistent with tissue residency and active tumour antigen engagement rather than terminal dysfunction. This nuanced immune phenotype indicates that DFI recalibrates T cell states towards a more vigilant, engaged profile capable of persisting and exerting cytotoxic effects in the tumour microenvironment.
The proliferative fraction of naive-like tumour antigen-specific CD8+ T cells expanded nearly twofold, corroborating the notion of enhanced T cell recruitment and priming. Correspondingly, T-cell receptor (TCR) repertoire diversity, assessed by the Shannon diversity index across both antigen-specific and bystander compartments, increased significantly following DFI therapy. Such broadened clonal diversity may underlie superior immune adaptability and capacity to respond to heterogeneous tumour antigens.
Collectively, these findings provide compelling evidence that transient hepatic reconstitution of trophic factors can revitalize multiple facets of immune functionality in aged hosts. By fostering a more robust and diverse tumour-specific T cell response, this strategy effectively bridges the gap in immunotherapy responsiveness observed with ageing. Importantly, the liver-targeted mRNA-LNP delivery system offers a clinically translatable platform for such immunomodulatory interventions.
Importantly, the work aligns with emerging paradigms recognizing the liver’s central regulatory role in systemic immunity and inflammation. By harnessing the liver as a biofactory for immune-enhancing proteins, this approach circumvents limitations posed by direct systemic cytokine delivery, which often entails toxicity and off-target effects. Consequently, liver-directed mRNA therapeutics may open new avenues for rejuvenating aged immune systems in cancer and beyond.
This research underscores an exciting frontier where transient, organ-specific molecular interventions can recalibrate the immune system, counteracting intrinsic ageing defects that dampen therapeutic efficacy. As immune checkpoint therapies continue to revolutionize oncology, such innovations are critical to expanding their benefits to elderly patients, who represent a growing demographic with the highest cancer burden.
Future studies will undoubtedly probe the precise trophic factor combinations and delivery kinetics optimally required for immune reconstitution, as well as evaluate long-term safety and efficacy in diverse tumour models. Moreover, integration with other immune-enhancing modalities could yield synergistic benefits, establishing multifaceted regimens tailored to overcome the multifactorial nature of immunosenescence.
In summary, this pioneering investigation illuminates the transformative potential of hepatic trophic factor reconstitution as a strategy to restore aged immunity and amplify antitumour T cell responses. It pioneers a paradigm shift in addressing age-associated immunotherapy resistance and offers a beacon of hope for enhancing cancer treatment outcomes in elderly patients through innovative mRNA therapeutics.
Subject of Research: Age-related immune dysfunction; enhancement of antitumour immunity via hepatic trophic factor reconstitution.
Article Title: Transient hepatic reconstitution of trophic factors enhances aged immunity.
Article References:
Friedrich, M.J., Pham, J., Tian, J. et al. Transient hepatic reconstitution of trophic factors enhances aged immunity. Nature (2025). https://doi.org/10.1038/s41586-025-09873-4
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41586-025-09873-4
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