Since the success of immune checkpoint blockade and chimeric antigen receptor T cell therapy, over a dozen immunotherapies have been approved in the past few years, and thousands of immunotherapeutics are currently in the development pipeline. However, immunotherapy benefits only a small fraction of cancer patients with identified tumor antigens and/or well-accessible tumors. New therapeutic strategies are needed to improve the efficacy of immunotherapeutics in broader patient populations with hard-to-reach, unidentified tumors. An approach gaining interest in the immuno-oncology community is to treat locatable and accessible tumors locally and stimulate antitumor immunity in situ to exert systemic effects against distant tumors.To develop an effective local immunotherapy, we have produced a polyethyleneimine derivative (2E’), which activates immune cells and co-delivers Paclitaxel (PTX), a hydrophobic immunogenic cell death inducer, and PD-L1 siRNA (siPD-L1) or cyclic dinucleotide (CDN), immunomodulatory nucleic acids or nucleotides. The immunoactive polymeric assembly 2E’/PTX/siPD-L1 was developed and characterized by transmission electron microscopy. The cytotoxicity, cellular uptake, PD-L1 silencing, and immunostimulatory effects of 2E’/PTX/siPD-L1 were tested on immune cell (bone marrow-derived dendritic cells) and murine cancer cells (CT26 colorectal carcinoma). The antitumor effects of intratumorally injected 2E’/PTX/siPD-L1 and 2E’/PTX/CDN were evaluated in female Balb/c mice bearing CT26 tumor. Surviving tumor-free mice were re-challenged with live cells on the contralateral side to test if systemic antitumor immunity was established. We show that a single local administration of 2E’/PTX/siPD-L1 or 2E’/PTX/CDN induces strong antitumor immunity, resulting in immediate regression of large established tumors, tumor-free survival, and the resistance to tumor rechallenge in a CT26 tumor model. This study supports that effective in-situ induction of antitumor immunity can lead to systemic protection from distant and recurrent diseases. 2E’/PTX/siPD-L1 and 2E’/PTX/CDN complexes are promising delivery systems for local cancer immunotherapy.