Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with high morbidity and mortality, which seriously threatens the health and life expectancy of patients. The traditional methods of treatment by surgical ablation, radiotherapy, chemotherapy, and more recently immunotherapy have not given the expected results in HCC. New integrative combined therapies, such as photothermal, photodynamic, photoimmune therapy (PTT, PDT, PIT), and smart multifunctional platforms loaded with nanodrugs were studied in this review as viable solutions in the synergistic nanomedicine of the future. The main aim was to reveal the latest findings and open additional avenues for accelerating the adoption of innovative approaches for the multi-target management of HCC. High-tech experimental medical applications in the molecular and cellular research of photosensitizers, novel light and laser energy delivery systems and the features of photomedicine integration via PDT, PTT and PIT in immuno-oncology, from bench to bedside, were introspected. Near-infrared PIT as a treatment of HCC has been developed over the past decade based on novel targeted molecules to selectively suppress cancer cells, overcome immune blocking barriers, initiate a cascade of helpful immune responses, and generate distant autoimmune responses that inhibit metastasis and recurrences, through high-tech and intelligent real-time monitoring. The process of putting into effect new targeted molecules and the intelligent, multifunctional solutions for therapy will bring patients new hope for a longer life or even a cure, and the fulfillment of the myth of Prometheus.