With the development of multimedia technology, online social media has become a major medium for people to access news, but meanwhile, it has also exacerbated the dissemination of multi-modal fake news. An automatic and efficient multi-modal fake news detection (MFND) method is urgently needed. Existing MFND methods usually conduct cross-modal information interaction at later stage, resulting in insufficient exploration of complementary information between modalities. Another challenge lies in the differences among news data from different domains, leading to the weak generalization ability in detecting news from various domains. In this work, we propose an efficient Cross-modal Prompt Learning with Semantic enhancement method for Domain-robust fake news detection (CPLSD). Specifically, we design an efficient cross-modal prompt interaction module, which utilizes prompt as medium to realize lightweight cross-modal information interaction in the early stage of feature extraction, enabling to exploit rich modality complementary information. We design a domain-general prompt generation module that can adaptively blend domain-specific news features to generate domain-general prompts, for improving the domain generalization ability of the model. Furthermore, an image semantic enhancement module is designed to achieve image-to-text translation, fully exploring the semantic discriminative information of the image modality. Extensive experiments conducted on three MFND benchmarks demonstrate the superiority of our proposed approach over existing state-of-the-art MFND methods.