Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. Here we perform integrative transcriptomic and proteomic analyses on emerging immuno-oncology targets across multiple clinical cohorts of melanoma under anti-PD-1 treatment, on both bulk and single-cell levels. We reveal a surprising role of tumor-intrinsic SIRPA in enhancing antitumor immunity, in contrast to its well-established role as a major inhibitory immune modulator in macrophages. The loss of SIRPA expression is a marker of melanoma dedifferentiation, a key phenotype linked to immunotherapy efficacy. Inhibition of SIRPA in melanoma cells abrogates tumor killing by activated CD8+ T cells in a co-culture system. Mice bearing SIRPA -deficient melanoma tumors show no response to anti-PD-L1 treatment, whereas melanoma-specific SIRPA overexpression significantly enhances immunotherapy response. Mechanistically, SIRPA is regulated by its pseudogene, SIRPAP1. Our results suggest a complicated role of SIRPA in the tumor ecosystem, highlighting cell-type-dependent antagonistic effects of the same target on immunotherapy. [Display omitted] • High SIRPA expression correlates with response to anti-PD-1 treatment in melanoma • The loss of SIRPA expression is a key marker of melanoma dedifferentiation • Tumor-specific SIRPA overexpression enhances anti-PD-L1 response • Multiple mechanisms affect SIRPA heterogeneity, including SIRPAP1 co-regulation Zhou et al. reveal that tumor-intrinsic SIRPA can enhance the sensitivity to anti-PD-1 treatment in melanoma patients, whereas macrophage SIRPA has a well-established role as a major inhibitory modulator in antitumor immunity. This study highlights that the same target in different cell types can have antagonistic effects on immunotherapy. [ABSTRACT FROM AUTHOR]