Soluble Oncoimmunome Signatures Predict Muscle Mass Response to Enriched Immunonutrition in Cancer Patients: Subanalysis of a Multicenter Randomized Clinical Trial

Background/Objectives: Enriched oral nutritional supplementation (ONS) has been shown to increase muscle mass in cancer patients. This study aims to identify the immunomodulatory effects and predictive biomarkers associated with this intervention. Methods: The soluble levels of 92 immune- and oncology-related mediators were determined before and after an intervention (8 weeks) in 28 patients with cancer receiving either a standard (n = 14) or an enriched ONS (n = 14) using the Olink proteomics analysis pipeline (Olink® Target 96 Immuno-Oncology panel (Uppsala, Sweden)) Results: Patients receiving enriched ONS experienced an average weight gain of 1.4 kg and a muscle mass increase of 2.2 kg after 8 weeks, both statistically significant (p < 0.05), while no such improvements were observed in the standard ONS group. Inflammatory markers TRAIL and LAMP3 were significantly reduced, along with an increase in Gal-1, suggesting lower inflammation and enhanced myogenic differentiation. However, patients who failed to gain muscle mass with the enriched formula showed a more aggressive inflammatory profile, characterized by higher serum levels of soluble MUC16, ARG, and IL12RB1. Interestingly, muscle mass gain could be predicted before the intervention, as responders had lower baseline levels of PGF, CD28, and IL12RB1. These differences were specific to recipients of the enriched ONS, confirming its immunomodulatory effects. Conclusions: Our findings support the use of enriched oral nutritional supplementation (ONS) as an effective strategy not only to enhance caloric and protein intake but also to promote anabolism and preserve muscle mass in cancer patients. The identification of immune profiles suggests that specific biomarkers could be used to predict which patients will benefit most from this type of intervention. This may allow for the implementation of personalized immunonutrition strategies that optimize resource allocation and improve clinical outcomes, particularly in vulnerable populations at risk of cachexia.