From intracellular drivers to immune modulators: emerging paradigms in oncogenic pathway-directed immunotherapy optimization

Cancer immunotherapy has revolutionized cancer treatment, offering durable responses in a subset of patients. Despite this progress, cancer cells have developed sophisticated mechanisms to evade immune surveillance, including genetic mutations, activation of immune escape pathways, alterations in the tumor microenvironment, and metabolic reprogramming. Additionally, the immune system’s ability to effectively target cancer cells can be compromised by immune tolerance and functional exhaustion. There is growing evidence that abnormal activation of cancer signaling pathways, such as the Wnt/β-catenin, Notch, JAK/STAT, p53, and PTEN pathways, acts independently or through crosstalk to form complex regulatory networks that influence tumor immune escape, the therapeutic response, and immune resistance. Consequently, elucidating the mechanisms by which these signaling pathways contribute to tumor immune escape is essential for optimizing current immunotherapy regimens and developing novel therapeutic strategies. Targeting these pathways in combination with immunotherapy represents a promising approach to overcome immune resistance and enhance treatment efficacy. The integration of pathway modulation with immunotherapeutic interventions may reveal new avenues for more effective and durable cancer treatments.