Resistance to PD-1 immunotherapy presents a significant challenge in cancer treatment, often associated with alterations in the tumor microenvironment and tumor-infiltrating lymphocytes (TILs) after treatment. Immune cell profiling in various tumor models revealed variations in TIL frequencies, with changes observed during cancer progression. Investigation of PD-1 resistant models, induced by hPD-1 antibody retreatment and observed in aged mice, demonstrated distinct mechanisms of resistance, including alterations in TIL composition and increased inhibitory myeloid-derived suppressor cell (MDSC) populations. These findings underscore the importance of TIL analysis in predicting responsiveness to PD-1 therapy and guiding treatment approaches.