Mechanistic insights of cancer immunology have led to the development of immune checkpoint blockade therapy (ICBT), which has elicited a remarkable clinical response in some cancer patients. Increasing evidence suggests that activation of oncogenic pathways, such as RAS/RAF/MAPK and PI3K signaling, impairs the antitumor immune response. Such oncogenic signaling, in turn, activates many inhibitory factors, including expression of immune checkpoint genes—allowing active infiltration of immunosuppressive cells into the tumor environment and inducing resistance against T-cell killing. In preclinical tumor models, effective targeting of oncogenic pathways has enhanced the response to ICBT. Ongoing clinical trials are now evaluating combination therapy (i.e., the use of oncogenic pathway inhibitors in combination with ICBT). However, more translational and clinical research is needed, to optimize ICBT doses and sequence, minimize toxicity, and assess the impact on study participants of certain genetic backgrounds. Also, it is crucial to understand whether wild-type tumors with elevated oncogenic signaling will respond to combination therapy. Insights gained through current and future translational studies will provide the scientific premise and rationale to target 1 or more oncogenic pathways in ICBT-resistant tumors, thus enabling more human patients to benefit from combination therapy.

癌症免疫学的机理见解导致了免疫检查点封锁疗法（ICBT）的发展，该疗法在某些癌症患者中引起了显着的临床反应。越来越多的证据表明，致癌途径（例如RAS / RAF / MAPK和PI3K信号传导）的激活会削弱抗肿瘤免疫反应。这种致癌信号转而激活许多抑制因子，包括免疫检查点基因的表达-允许免疫抑制细胞主动渗透到肿瘤环境中，并诱导对T细胞杀伤的抵抗力。在临床前肿瘤模型中，有效靶向致癌途径已增强了对ICBT的反应。现在正在进行的临床试验正在评估联合治疗（即，将致癌途径抑制剂与ICBT联合使用）。然而，需要进行更多的翻译和临床研究，以优化ICBT剂量和序列，最大程度地降低毒性，并评估某些遗传背景对研究参与者的影响。同样，至关重要的是要了解致癌信号增强的野生型肿瘤是否会对联合治疗产生反应。通过当前和将来的转化研究获得的见识将为靶向ICBT耐药性肿瘤中的1种或多种致癌途径提供科学前提和理论依据，从而使更多的人类患者受益于联合治疗。