Core Viewpoint - The article discusses the promising results of fecal microbiota transplantation (FMT) combined with immunotherapy in treating non-small cell lung cancer (NSCLC), melanoma, and metastatic renal cell carcinoma (mRCC), highlighting its potential to overcome resistance to PD-1 therapy and improve patient outcomes [2][3][4]. Group 1: FMT and Immunotherapy in NSCLC and Melanoma - The FMT-LUMINate trial demonstrated an objective response rate (ORR) of 80% (16/20) in NSCLC and 75% (15/20) in melanoma, achieving the primary endpoint [8]. - Safety assessments indicated no grade 3 or higher adverse events in the NSCLC cohort, while 65% of melanoma patients experienced grade 3 or higher adverse events [8]. - The study found that responders had a unique gut microbiome composition post-FMT, with significant reductions in specific bacterial species associated with non-responders [9]. Group 2: FMT in Metastatic Renal Cell Carcinoma - The PERFORM trial showed that 50% (10/20) of mRCC patients experienced grade 3 immune-related adverse events, with no severe FMT-related toxicities reported [11][14]. - The objective response rate was 50% (9/18), including 11% (2/18) achieving complete response, with most responders not experiencing severe immune-related adverse events [14]. - Improvements in gut microbiome diversity were linked to reduced toxicity and enhanced treatment response, while the presence of specific bacteria correlated with higher immune-related adverse events [15][16]. Group 3: FMT Combined with Pembrolizumab and Axitinib - The TACITO trial evaluated the efficacy of donor-derived FMT in mRCC patients receiving pembrolizumab and axitinib, with a primary endpoint of disease progression-free survival [18][21]. - Although the primary endpoint was not met, the donor FMT group showed a significantly longer median progression-free survival of 24.0 months compared to 9.0 months in the placebo group [22]. - The donor FMT group had an ORR of 52%, while the placebo group had 32%, indicating potential benefits of selective donor FMT in enhancing immunotherapy outcomes [22].

Core Viewpoint - Fecal Microbiota Transplantation (FMT) is increasingly used as an intervention method, but it may lead to unexpected negative health consequences due to microbial mismatches during the process [5][12][14]. Group 1: FMT Overview - FMT involves transferring microbiota from healthy donors to patients to restore gut microbiome balance, primarily using anaerobic microbes from the colon [2]. - The FDA has approved FMT for treating recurrent Clostridium difficile infections, but its efficacy and mechanisms in other diseases remain unclear [3]. Group 2: Research Findings - A study published in Cell highlights that microbial mismatches during FMT can lead to persistent off-target metabolic and immunomodulatory effects [4]. - The research indicates that anaerobic microbes from the colon may colonize the small intestine post-FMT, altering the local gut environment and potentially leading to negative health impacts [6][11]. Group 3: Methodological Insights - The study suggests that performing FMT via colonoscopy may help avoid unexpected outcomes compared to oral or upper gastrointestinal endoscopic methods [7][16]. - Experiments on mice showed that different transplantation methods (jejunum vs. cecum vs. fecal) resulted in varying impacts on metabolic pathways and immune responses, with jejunum transplants being more beneficial for host metabolism [10]. Group 4: Implications for Future Research - The findings emphasize the need for objective measures to evaluate both short-term and long-term consequences of FMT [15]. - There is a call to reconsider the best administration routes for FMT, weighing the benefits of colonoscopy against other methods to mitigate risks [16].