Cancer is an evolutionary process shaped by selective pressure from the microenvironments. However, recent studies reveal that certain tumors undergo neutral evolution where there is no detectable fitness difference amongst the cells following malignant transformation. Here, through computational modeling, we demonstrate that negative frequency-dependent selection (or NFDS), where the immune response against cancer cells depends on the clonality of neoantigens, can lead to an immunogenic landscape that is highly similar to neutral evolution. Crucially, NFDS promotes high antigenic heterogeneity and early immune evasion in hypermutable tumors, leading to poor responses to immune checkpoint blockade (ICB) therapy. Our model also reveals that NFDS is characterized by a negative association between average clonality and total burden of neoantigens. Indeed, this unique feature of NFDS is common in the whole-exome sequencing (WES) datasets (357 tumor samples from 275 patients) from four melanoma cohorts with ICB therapy and a non-small cell lung cancer (NSCLC) WES dataset (327 tumor samples from 100 patients). Altogether, our study provides quantitative evidence supporting the theory of NFDS in cancer, explaining the high prevalence of neutral-looking tumors. These findings also highlight the critical role of frequency-dependent selection in devising more efficient and predictive immunotherapies.