Multidrug resistance (MDR), a multiple cross-resistance towards different anticancer drugs, limits the success of chemotherapy. One of the main mechanisms of MDR is the overexpression of integral membrane transporters, belonging to the ATP binding cassette (ABC) transporter family, such as P-glycoprotein (Pgp). We previously demonstrated that Pgp impairs the proper recognition of tumor cells by immune system, making chemoresistant cells also immunoresistant. The molecular basis of this double resistance are not known. Moreover, there are no chemosensitizing compounds with the dual property of inducing selective cytotoxicity in MDR cells (i.e. producing a paradoxical hypersensitivity known as “collateral sensitivity”, CS, of MDR cells) and activating the response of the host immune system. We hypothesize that the critical intracellular organelles that can be targeted to induce CS and restore immunosensitization are endoplasmic reticulum (ER), mitochondria and ER membrane-associated to mitochondria (MAM).