Hydrophobic neoantigens are more immunogenic because they are better presented by the major histocompatibility complex and better recognized by T cells. Tumor cells can evade the immune response by expressing checkpoints such as programmed death ligand 1. Checkpoint blockade reactivates immune recognition and can be effective in diseases such as melanoma, which harbors a high tumor mutational burden (TMB). Cancers presenting low or intermediate TMB can also respond to checkpoint blockade, albeit less frequently, suggesting the need for biological markers predicting response. We calculated the hydrophobicity of neopeptides produced by probabilistic in silico simulation of the genomic UV exposure mutational signature. We also computed the hydrophobicity of potential neopeptides and extent of UV exposure based on the UV mutational signature enrichment (UVMSE) score in The Cancer Genome Atlas (TCGA; N = 3543 tumors), and in our cohort of 151 immunotherapy‐treated patients. In silico simulation showed that UV exposure significantly increased hydrophobicity of neopeptides, especially over multiple mutagenic cycles. There was also a strong correlation (R² = 0.953) between weighted UVMSE and hydrophobicity of neopeptides in TCGA melanoma patients. Importantly, UVMSE was able to predict better response (P = 0.0026), progression‐free survival (P = 0.036), and overall survival (P = 0.052) after immunotherapy in patients with low/intermediate TMB, but not in patients with high TMB. We show that higher UVMSE scores could be a useful predictor of better immunotherapy outcome, especially in patients with low/intermediate TMB, likely due to increased hydrophobicity (and hence immunogenicity) of neopeptides.