Advancing Immunotherapy in the Elderly: Overcoming Metabolic and Inflammatory Barriers

Zechen Wang¹Pin Guo¹Chao Liu²Guang-Liang Chen^3*

• ¹The Affiliated Hospital of Qingdao University, Qingdao, China
• ²Dana-Farber Cancer Institute Department of Data Sciences, Boston, United States
• ³Shanghai Cancer Center, Fudan University, Shanghai, China

treating age as a covariate to interrogate the aging host biology and offer strategies to sharpen diagnostics, improve therapeutic efficacy, and mitigate debilitating systemic symptoms. A prevailing concern in geriatric oncology has been that immunosenescence may render immune checkpoint inhibitors (ICIs) ineffective in older patients. The work presented in this topic provides a powerful rebuttal to this dogma. A multicenter observational analysis by Drobniak et al.(https://doi.org/10.3389/fonc.2025.1617743) evaluated the combination of nivolumab and ipilimumab in older adults with metastatic renal cell carcinoma (mRCC). Their findings provide reassuring real-world evidence: patients aged ≥65 years demonstrated superior outcomes compared to younger patients (<65 years), with longer progression-free survival, higher ORR/DCR, and acceptable immune-related toxicity profiles. This challenges the conventional wisdom that age alone should be a limiting factor for immunotherapy, proving that an "aged" immune system remains remarkably capable of being harnessed against cancer. These findings support targeted anti-inflammatory approaches that directly block a key cytokine pathway as an effective bridge to maintain or resume cancer treatment. Effective treatment begins with accurate and early detection; a need that is particularly acute in frail elderly patients for whom invasive procedures carry higher risk. In this Topic, the study on exosome-derived lncRNA PITPNA-AS1 in pleural effusions by Chen et al.(https://doi.org/10.3389/fimmu.2025.1539557) shows how a liquid-biopsy signal can aid differential diagnosis across lung cancer subtypes and track disease burden. Their research shows that exosomal lncRNA PITPNA-AS1 distinguishes malignant from benign lung conditions with high sensitivity and specificity across several lung-cancer subtypes. Mechanistically, PITPNA-AS1 binds FMR1, blocks its ubiquitination, and thereby stabilizes the protein, an interaction that may drive oncogenesis. Consequently, the study moves beyond diagnostics: by implicating PITPNA-AS1 in tumorigenesis, it reveals a potential therapeutic target at the nexus of cellular metabolism and cancer signaling. Overall, PITPNA-AS1 emerges as a promising, non-invasive biomarker; future work should assess its prognostic value and longitudinal performance. Collectively, the studies in this Topic show that we can expand the appropriate use of ICIs in older adults, modulate inflammatory and angiogenic barriers to improve perioperative efficacy, and deploy non-invasive diagnostics that ease the burden on frail patients. The path forward is not to withhold therapy based on chronological age, but to personalize care by integrating immunosenescence, inflammaging, and immunometabolic considerations, so that more older patients can both receive and benefit from cancer immunotherapy.