Metastatic cold tumors with a large primary site (i.e., >5 cm) represent an open issue as surgery is often excluded and immunotherapy (IT) have reported limited response, because of the immunosuppression present in their microenvironments (cold TME). Due to their dimensions and hypoxia, large tumors are especially radioresistant, requiring to be irradiated with higher doses, not deliverable by conventional radiotherapy (RT) without an increased toxicity to the surrounding tissues. Even stereotactic body radiation therapy (SBRT) is excluded, as it is usually limited to targets with a diameter below 5 cm. Lattice Radiation Therapy (LRT) is a novel RT technique, based on an inhomogeneous dose delivery, that allows to safely achieve an outstanding cytoreduction of large lesions by concurrently administering ablative high doses inside the tumor and controlled doses near the adjacent organs at risk (OARs). In addition, preliminary data suggest that LRT might reengineer tumor microenvironment (TME), making it more immunogenic, and it could boost the host immune system response against irradiated and not irradiated lesions. Hence, LRT could represent an interesting strategy to deal with localized and widespread diseases in metastatic cold tumors with a large primary lesion.Impact statement: Lattice radiation therapy (LRT) is an innovative type of spatially fractionated radiation therapy. In addition to an outstanding cytoreduction, LRT is hypothesized to prime a vigorous immune reaction that could be exploited in cold tumors to rejecet metastatic cancer cells.

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