Understanding the interplay between immune and stromal cells in the tumor microenvironment is essential for developing effective cancer therapies and preventing relapses. In this review, starting with the basics of tumor immunology and a historical review from cancer chemotherapy to current immunotherapy, in the context of precision medicine, we focus on immunotherapies based on genetically modified macrophages, and chimeric T-cell antigen receptor (CAR), highlighting the similarities and differences between TCR-endogenous signaling and CART-dependent signaling at the immune synapse, presenting all the generations that have been developed briefly, followed by NK cell-dependent CAR therapeutic approaches where a comparison is established, analyzing their respective advantages and drawbacks. Targeting the tumor-immune microenvironment has become central to cancer treatment, with combinatorial therapies applied and assessed as a feasible strategy for this complex group of diverse pathologies. In this context, modulating the immune synapse, rewiring immune cell metabolism, and developing genetically engineered immune cells have emerged as promising approaches that open novel avenues for treating and managing cancer patients. This review offers a holistic, historical view of state-of-the-art molecular approaches, along with insights into future perspectives and current limitations of the technologies supporting immunotherapy in molecular oncology.