Abstract: The inhibition of immune regulatory checkpoints, such as CTLA-4 and PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade(ICB). Furthermore, the tumor-related factors that affect the efficacy of ICB include mutant load, carcinogenic signal, DNA MMR deficiency, pre-death cell stress and injury-related molecular pattern, PD-L1 expression and other factors; non-tumor-related factors include peripheral and tumor lymphocytes, viruses and other factors. The factors related to ICB resistance mainly include metabolism, epigenetic silencing chemokine secretion, type Ⅰ IFN signaling, intestinal micro-organisms, chronic infection, age, smoking history and so on. A variety of therapeutics are being combined with ICBs to reduce this heterogeneity by improving the probability, duration and potency of clinical activity; many of these have seen success, albeit often in parallel with increased toxicities.