Chronic inflammation and immune suppression characterizes the tumor microenvironment of most cancer patients. Therefore, we propose to develop an innovative gene-based technology platform to modulate immune cells that support this environment with the aim to manipulate the host’s immune system and improve antitumor immunity. As a proof-of-concept, we will focus on type 2 tumor-associated macrophages (TAM2), since they support tumor growth, invasion and metastasis. Moreover, TAM2 are linked to therapy resistance and poor prognosis, making them promising targets for future antitumor therapy. We will design gene-based nanobody-drug conjugates (NDCs), consisting of a TAM2-targeting nanobodies genetically linked to TAM2-modulating proteins, which will either deplete or revert the pro-tumor traits of TAM2. We will generate lentiviral vectors and mRNA that encode the NDCs, as their intratumoral delivery is an elegant approach to obtain local and continuous production of proteins. We will test the NDCs in vitro for their efficacy to deplete or modulate TAM2 of mouse and human origin. Moreover, their effect on tumor immunity and tumor growth will be evaluated in vivo in primary and metastatic tumor models. We expect that this gene-based approach of targeting immune cells within the tumor nest will enable greater progress in the treatment of tumors and ultimately lead to improved outcomes for cancer patients.